Clathrin-mediated endocytosis (Homo sapiens)

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10, 12, 15, 25, 29...15, 16, 36, 61, 64...4, 19, 25, 26, 37...2, 5, 32, 34, 58...15, 30, 36, 45, 109...34, 56, 60, 64, 106...1, 4, 18, 66, 76...26, 50, 52, 54, 74...80, 13814, 71, 75, 8419, 39, 44, 63, 65...8, 46, 59, 98, 1009, 13, 22, 51, 10615, 36, 109, 125, 15012, 23, 34, 76, 86...3, 14, 47, 48, 71...49, 106, 108, 126, 14017, 29, 63, 72, 91...49, 106, 108, 126, 1406, 8, 9, 12, 13, 20...32, 34, 44, 65, 77...clathrin-coated endocytic vesiclecytosolAGTR1 ARPC4 CLTC STON1 EPS15 p-Y371-CBL EPS15 CLTA UBB(153-228) SH3GL1 ADR CLTCL1 ARPC5 GRB2-1 f-actin UBB(77-152) UBC(457-532) AP2S1 p-Y850 EPS15 NAd PACSIN2 GRB2-1 VAMP2 AMPH p-DVL2 FNBP1 FZD4 AMPH SH3GL3 ITSN1 AGFG1 STON2 EPN1 VAMP8 FCHO2 PI4PBIN1 PL UBC(381-456) GTP NECAP1 EPS15 DAB2 p-DVL2 UBC(381-456) AP2A2(1-939) AP2A2(1-939) AP2M1 STON2 TRIP10 pS-ADRB2 REPS2 AP2A2(1-939) ARPC2 REPS1 UBB(77-152) FCHO1 DAB2 CLTA AP2S1 STAM REPS2 PI(4)P:p-T156AP-2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinGAK REPS1 ARPC1A FNBP1 SYT8 CLTA EGF AMPH SH3GL3 AP2A1 UBB(1-76) ARPC1A CHRM2 AAK1 CTTN HIP1 AP2A1 AP2B1 LDLRAP1 AP2S1 EPS15L1 PICALM AP-2 dileucine-containing cargo UBA52(1-76) CHOL CHRM2 HIP1R PACSIN2 CLTCL1 AGFG1 LRP2 PACSIN1 ARRB2 BIN1 p-6Y-EGFR NECAP1 APOB(28-4563) UBC(609-684) HIP1R PACSIN2 PL N-WASP FZD4 VAMP7 SNX18 ACTR3 CLTA VAMP7 p-Y850 EPS15 UBC(1-76) EPS15 REPS2 EPS15STAM ATP DAB2 CLTC ACTR3 SYT2 UBB(153-228) EPN1 ARPC4 STAM2 UBC(381-456) ARRB1 ACTR2 ITSN1 p-DVL2 ARRB1 ARPC3 AVP(20-28) ADR CLTC UBC(381-456) LDLR HIP1 AP2A1 AP2S1 AP2M1 AP2A1 AP-2 YXXPhi cargo LRP2 RPS27A(1-76) VAMP8 UBC(229-304) PI(4)P:p-T156AP-2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinGGC-RAB5:GTP:GAPVD1AP2M1 CLTB SYT9 ARPC4 STON1 N4GlycoAsn-PalmS WNT5A(36-380) AP-2 dileucine-containing cargo SYT2 AP2A2(1-939) SYNJ1 p-T156 AP2M1 UBC(381-456) HIP1R dimerITSN1 AP2S1 TACR1 STAM2 ARRB1 PACSIN1 CLTA PACSIN1 SYT1 GAPVD1 ADPCHOL UBC(229-304) UBB(153-228) PL AP2A2(1-939) AVP(20-28) FCHO1 SYT9 AP2S1 p-DVL2 NECAP1 NECAP2 SYT1 FNBP1 UBB(1-76) SYT9 PACSIN2 AP2S1 PI4PGGC-RAB5C GRB2-1 AP-2 dileucine-containing cargo p-T156 AP2M1 UBA52(1-76) SNAP91 GRB2-1 N4GlycoAsn-PalmS WNT5A(36-380) TRIP10 PI4PEGF PI(4,5)P2 UBC(229-304) DNM3 AP2A1 EPS15L1 STAM AP2A1 ARPC2 REPS2 CLTA ACTR3 UBC(229-304) DNM1 AP2A1 CLTB STAM AVP(20-28) PACSIN1 SYNJs,OCRLUBB(1-76) CLTB FNBP1 FZD4 REPS1 GAK,DNAJC6AP2M1 CHOL VAMP3 VAMP3 REPS2 N4GlycoAsn-PalmS WNT5A(36-380) STAM2 ADR LDLRAP1 SYT2 ACTR2 DAB2 EPN2 cholesterol esters REPS1 p-6Y-EGFR UBC(305-380) SNX9 GGC-RAB5C BIN1 p-Y371-CBL AP2M1 p-6Y-EGFR AGTR1 CLTB BIN1 EPN2 DAB2 ITSN2 UBB(1-76) CHRM2 SH3GL2 AP2A1 EGF AP-2 dileucine-containing cargo GDP STON2 PI4P HGS STAM EPS15 PACSIN3 AP2B1 AP2B1 AMPH:BIN1ARPC1A AP2A1 CLTA SYT1 p-T156 AP2M1 RPS27A(1-76) UBC(533-608) CLTB UBC(457-532) REPS2 FZD4 EPN2 p-DVL2 VAMP2 p-DVL2 SYT9 N4GlycoAsn-PalmS WNT5A(36-380) EPS15L1 STON1 CLTC SGIP1 TACR1 HIP1 AP2A1 p-Y371-CBL UBC(1-76) CLTA HSPA8 CLTB UBB(1-76) VAMP8 AP2A1 HIP1 NAd CTTN SH3KBP1 SYT11 SH3GL1 cholesterol esters ACTR3 AGFG1 PICALM CHRM2 SH3GL3 AGTR1 AP2M1 STON2 SH3GL3 Cargo recognitionforclathrin-mediatedendocytosisCHOL AP2M1 CLTCL1 FNBP1L AP2A1 UBC(229-304) UBC(381-456) AP2B1 SYT8 VAMP3 ACTR3 AVP(20-28) ARPC1A UBC(77-152) N-WASP VAMP8 EPN1 GRB2-1 ATP SGIP1HGS AP-2 dileucine-containing cargo CLTC UBB(1-76) HIP1 ATP p-Y850 EPS15 p-Y371-CBL AP2B1 EGF CHOL AMPH REPS1 AP2M1 AMPH UBC(153-228) AVPR2 FZD4 CLTCL1 PL APOB(28-4563) GDP SYT2 UBC(533-608) AMPH ARRB2 UBB(153-228) EPN1 GRB2-1 AVPR2 UBC(1-76) TRIP10 HIP1 pS-ADRB2 VAMP3 UBC(1-76) SYT2 NAd ITSN2 UBC(457-532) CLTB CLTC PACSIN3 SNX9 NECAP2 AP2B1 PIP5K1CAP2M1 EPS15L1 AP2A2(1-939) AP2A1 SH3KBP1 VAMP3 TACR1 p-Y371-CBL STON1 FNBP1L SH3GL3 ATPCLTA AP2M1 AMPH NECAP1 TRIP10 APOB(28-4563) p-DVL2 ADR PI(4,5)P2:p-T156AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimersAP-2 dileucine-containing cargo ARPC5 AVP(20-28) f-actinPI(4,5)P2 PI(4)P:p-T156AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTP:SYNJsGAK ARRB2 APOB(28-4563) cholesterol esters p-AVPR2 SYNJ2 AGTR1 VAMP2 UBC(229-304) SYT2 CLTA DNM1 AAK1 ARPC1A CLTC AGTR1 DNM2 EPS15L1 DNM3 FCHO2 N4GlycoAsn-PalmS WNT5A(36-380) p-6Y-EGFR AGFG1 FNBP1L CHOL VAMP2 ARRB1 cholesterol esters CTTN AP2B1 UBC(609-684) STON1 REPS1 DAB2 UBB(1-76) SH3GL3 UBC(533-608) DNM1 SGIP1 UBB(77-152) NAd PACSIN2 NECAP1 ATP FCHO1,2 dimerSTAM SYT9 UBC(153-228) CLTC GRB2-1 TACR1 H2ONAd TAGs AP-2 dileucine-containing cargo APOB(28-4563) LDLRAP1 UBC(229-304) LDLRAP1 GGC-RAB5B AP2S1 VAMP8 EGF SH3GL2 PACSIN1 SNAP91 AVP(20-28) cholesterol esters AP2B1 EPN1 HIP1 PICALM HIP1 ITSN1 TAGs cholesterol esters AP2A2(1-939) p-AVPR2 p-Y850 EPS15 SH3KBP1 LDLRAP1 UBC(77-152) VAMP3 AP2M1 UBC(533-608) ACTR3 UBB(77-152) SGIP1 UBB(153-228) SH3GL2 SYNJ2 ITSN2 SYT9 NECAP2 SYT1 VAMP2 HGS AP-2 YXXPhi cargo ARFGAP1 AP2A2(1-939) p-Y371-CBL VAMP2 AP2A2(1-939) TACR1 AP2S1 UBC(609-684) UBC(533-608) PACSIN3 LRP2 CLTC SH3KBP1 UBC(1-76) CLTB ITSN2 STON2 FZD4 UBB(153-228) SYT11 CLTC AGTR1 SH3GL2 AP2B1 EPS15 N-WASP GRB2-1 ARPC5 CLTCL1 CLTB FNBP1 CLTA FZD4 AP2S1 HGS AP-2 dileucine-containing cargo SNAP91 LRP2 ARPC3 STON1 AP2A1 VAMP2 UBC(457-532) EPN1 AP2S1 SNAP91 UBC(77-152) PACSIN3 AP2S1 CLTA LDLR ITSN2 NECAP1 CLTC SNX18 REPS1 ARRB2 TACR1 AGTR1 AP2M1 CTTN TAGs GGC-RAB5B PI(4)P:p-T156AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilin:HSPA8:ATPp-AVPR2 pS-ADRB2 SYT11 ARPC5 FCHO1 OCRL TRIP10 NAd TAGs TRIP10 dimerSTON2 UBB(77-152) N-WASP AVP(20-28) AP2S1 H2OCLTCL1 HIP1R TRIP10 PI(4,5)P2:p-T156AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargop-Y371-CBL p-6Y-EGFR AP2M1 FNBP1L UBC(533-608) STAM2 AP-2 YXXPhi cargo PACSIN3 SYNJ2 PL SH3KBP1 ARRB1 EPS15 ITSN1 UBC(1-76) UBA52(1-76) p-Y850 EPS15 SYT1 VAMP2 ADR STON1 FNBP1L CLTCL1 STAM2 EGF OCRL VAMP8 AP2S1 PI(4,5)P2:p-T156AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1UBC(153-228) ARPC4 EPS15 SYT11 VAMP7 AP2S1 PI(4,5)P2:p-T156AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteinsFNBP1L dimerAPOB(28-4563) AAK1ARPC2 STAM2 PI4P CHRM2 AP2S1 HSPA8:ATPDNM3 SH3GL2 BIN1 p-DVL2 FNBP1L AP2A1 ARPC3 DNM2 p-DVL2 SNAP91 CHRM2 ADR LDLR ARPC4 NECAP1 UBC(609-684) p-Y371-CBL SYT2 STAM2 SH3GL2 SYT2 AP2B1 p-AVPR2 GAPVD1 GGC-RAB5:GTP:GAPVD1REPS2 UBC(609-684) UBB(77-152) DNM2 SH3GL2 EPN1 f-actin AP2M1 N4GlycoAsn-PalmS WNT5A(36-380) UBC(229-304) SH3GL2 p-T156 AP2M1 pS-ADRB2 STAM2 PACSIN3 EPN1 CHRM2 LDLRAP1 AP2M1 PI4P CHRM2 UBB(77-152) GGC-RAB5B PACSIN1 VAMP7 DNM1 ARRB1 AP2A1 TRIP10 FCHO2 PACSIN3 NECAP2 PACSIN2 p-Y371-CBL AP2A2(1-939) ITSN2 ARP2/3 complexp-T156 AP2M1 CLTB PICALM ARRB2 ARPC5 AP-2 YXXPhi cargo BIN1 UBC(229-304) STON1 N4GlycoAsn-PalmS WNT5A(36-380) HSPA8 LDLRAP1 AP-2 YXXPhi cargo STON2 ACTR3 PL HIP1R FCHO1 AGTR1 SYT8 REPS2 ATPDAB2 UBC(381-456) RPS27A(1-76) TAGs LRP2 UBB(77-152) p-DVL2 EPS15 CLTCL1 EGF ADR AVPR2 UBC(457-532) CLTA GDP PICALM ARPC2 CHOL UBC(305-380) PACSIN3 SH3KBP1 DNM3 clathrin triskelionARRB1 AP2S1 cholesterol esters SH3GL3 AP2M1 SYT1 EPN1 REPS2 p-AVPR2 APOB(28-4563) UBC(305-380) UBC(533-608) VAMP7 PACSIN2 SH3GL2 p-Y371-CBL ARPC4 REPS1 GGC-RAB5A PL TAGs WASL,CTTNARRB1 VAMP2 EGF ATP ARPC3 VAMP7 TAGs p-T156 AP2M1 PI(4,5)P2 CLASP proteins:cargoCHOL AP-2 dileucine-containing cargo SYT9 UBC(77-152) ARPC1A FZD4 AP2B1 HIP1R CLTC DAB2 p-T156 AP2M1 UBC(77-152) cholesterol esters NAd UBC(1-76) DNM3 ACTR2 FCHO2 PICALM p-6Y-EGFR UBA52(1-76) CLTCL1 EPS15L1 EPN1 DAB2 p-6Y-EGFR SYNJ2 UBA52(1-76) UBC(229-304) ARRB2 ARPC5 ARPC5 TAGs GGC-RAB5A SH3GL2 GTP pS-ADRB2 VAMP2 SYT1 cholesterol esters LRP2 ADR RPS27A(1-76) AP-2 dileucine-containing cargo ITSN1 UBC(457-532) BIN1 GTP PICALM CHRM2 ADR STAM EPN1 AVP(20-28) DNM2 VAMP3 SH3GL3 PACSIN1 p-T156 AP2M1 AP2B1 ITSN2 LRP2 AP-2 YXXPhi cargo p-Y850 EPS15 DNM:GDPNAd APOB(28-4563) OCRL SH3GL3 CLTC AGFG1 CLTC STAM2 UBC(305-380) GRB2-1 pS-ADRB2 AP2A2(1-939) AP2B1 GAK AP2B1 CLTCL1 AVP(20-28) AP2B1 FNBP1L UBC(381-456) HIP1 SYNJ2 TACR1 NECAP2 LDLRAP1 REPS1 SNX9 HGS UBC(305-380) SH3GL3 OCRL NAd pS-ADRB2 ITSN2 EPS15 SH3KBP1 UBC(457-532) LDLR STON2 CLTCL1 DNM2 ACTR3 APOB(28-4563) AP2B1 UBC(609-684) SYT8 LDLR AP2M1 NECAP1 SNX18 PACSIN dimersGGC-RAB5B ATP AP2S1 SGIP1 ADPVAMP8 EPS15 DNM1 PI(4,5)P2 ADP RPS27A(1-76) AGFG1 SNAP91 LDLRAP1 NECAP2 SYT8 CLTA STAM PICALM STON2 SH3GL1 REPS2 UBC(381-456) AAK1 VAMP8 AP2A1 AP2B1 PI4P pS-ADRB2 pS-ADRB2 TACR1 LRP2 AGTR1 AP2S1 SH3GL2 UBB(77-152) HGS STON1 SNAP91 SH3GL1 f-actin AVP(20-28) VAMP7 CLASP proteins:cargoSYT1 AGTR1 CTTN UBB(153-228) UBC(381-456) UBB(153-228) ARPC1A PL OCRL SYNJ1 p-DVL2 FNBP1L ACTR3 UBC(609-684) VAMP8 CLTC SGIP1 NECAP1 AAK1 UBC(305-380) STAM2 LDLR RPS27A(1-76) UBC(305-380) EPN2 GAK STAM SNX18 ARPC3 H2OSGIP1 PL EPS15 SYNJ1 CHRM2 DNM3 SH3GL3 AP2A2(1-939) VAMP2 STAM2 AP2A1 SYNJ2 TACR1 N4GlycoAsn-PalmS WNT5A(36-380) STON1 ATP AP2M1 DNAJC6 LDLRAP1 CTTN BIN1 p-Y371-CBL NECAP1 STON2 ARRB2 VAMP8 EPN2 UBC(305-380) CLTC ARPC4 SNAP91 p-Y371-CBL EPN1 AP2S1 TRIP10 VAMP7 EPN1 SNX18 UBC(153-228) SYT8 LDLR UBC(609-684) UBC(153-228) ARRB2 UBC(153-228) STAM ARF6 EPS15 AAK1 TAGs CLTA STON2 p-T156 AP2M1 AAK1 ATPCLTA ARRB2 ARPC1A SNX9 REPS1 EPS15 p-Y371-CBL UBA52(1-76) STAM UBB(1-76) TAGs SH3GL3 p-AVPR2 ATP AP2A1 SGIP1 STAM2 UBC(305-380) AP2A2(1-939) UBA52(1-76) CLTC AP2A2(1-939) AP2A2(1-939) PACSIN1 AAK1 p-Y371-CBL PL DNM1 ARPC5 AP2M1 CLTB RPS27A(1-76) CHOL f-actin EPN1 UBB(1-76) GDP AP2B1 SH3GL1 VAMP8 HGS LDLRAP1 AP2M1 UBC(533-608) LDLR p-Y850 EPS15 PL PL EPN2 LDLRAP1 p-6Y-EGFR GDP AVPR2 TAGs SNX9,18CTTN p-Y850 EPS15 DNAJC6 EPS15L1 SYNJ1 VAMP7 REPS1 SYT11 ARRB1 PICALM NECAP2 AGFG1 UBC(457-532) OCRL FNBP1 CLTA DNM3 AGTR1 ARPC4 GRB2-1 AP2S1 NECAP1 SYNJ1 SYT11 RPS27A(1-76) EPS15L1 SYT1 UBC(229-304) STON2 ITSN1 N-WASP ADR UBC(77-152) ARRB2 SH3GL3 UBB(1-76) GRB2-1 RPS27A(1-76) CLTB ARPC1A TACR1 EPN2 TRIP10 FNBP1 AP-2 ComplexADR ARRB1 DNM1 p-Y371-CBL ATP UBC(533-608) SNAP91 APOB(28-4563) HIP1 dimerAAK1 LDLR AP2A2(1-939) PI(4,5)P2 EPS15L1 EGF DAB2 OCRL AP2A2(1-939) LRP2 PI(4,5)P2 p-Y371-CBL LDLR GGC-RAB5A UBB(77-152) CHRM2 NECAP2 p-DVL2 REPS2 SYT8 ITSN2 EPS15 SGIP1 HGS f-actin AP2A2(1-939) AP-2 YXXPhi cargo UBC(229-304) EPN2 SYT9 p-6Y-EGFR HIP1R UBC(77-152) SYT2 PIK3C2APICALM p-Y850 EPS15 SH3GLsVAMP8 ACTR3 UBC(305-380) TAGs CLTC FNBP1 dimerCLTA SYT1 SYNJ1 REPS2 SH3KBP1 STON2 N4GlycoAsn-PalmS WNT5A(36-380) ARPC2 DAB2 UBC(609-684) EPS15L1 f-actin AP2B1 REPS2 CLTCL1 UBB(153-228) UBC(1-76) ITSN1 CLTA EPS15L1 SH3GL1 SNX18 SNX9 SYT8 AP2A1 FZD4 UBB(153-228) REPS1 PICALM ARRB2 VAMP7 CLTCL1 EGF p-Y850 EPS15 HGS UBC(1-76) UBC(1-76) ARPC2 VAMP3 SH3GL1 ITSN1 N-WASP AP2A2(1-939) SNAP91 NECAP2 CLTA AP-2 YXXPhi cargo UBB(77-152) APOB(28-4563) ITSN1 AVP(20-28) AAK1AP2A1 UBC(457-532) SYT2 UBA52(1-76) SYT8 EPN1 STON1 EPN1 AAK1 CLTCL1 ARPC5 SNAP91 AP2S1 ITSN1 PACSIN2 APOB(28-4563) CHOL CLTC pS-ADRB2 UBC(153-228) SYNJ2 p-AVPR2 VAMP7 FNBP1 SNX9 ACTR2 PI(4,5)P2:AP-2:clathrinDNM2 FZD4 BIN1 UBB(153-228) PI(4,5)P2:AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1EPN1 CLTA HIP1R AP-2 dileucine-containing cargo CHRM2 VAMP8 SH3GL2 NECAP2 UBC(305-380) VAMP3 VAMP7 p-Y371-CBL SYT9 DNAJC6 AP2A1 UBB(153-228) HGS N4GlycoAsn-PalmS WNT5A(36-380) AP2B1 p-Y850 EPS15 RPS27A(1-76) CLTA AP2S1 VAMP3 STAM HIP1R AP2B1 FNBP1 SNX18 SYT8 NAd pS-ADRB2 SNX9 CTTN SYT8 LDLR VAMP3 RPS27A(1-76) TAGs UBC(229-304) PI(3,4)P2CLTB FCHO2 UBC(1-76) PACSIN3 GGC-RAB5C pS-ADRB2 UBC(77-152) PACSIN3 ARPC2 NECAP1 AP2M1 NECAP1 UBC(229-304) ACTR2 AGFG1 PACSIN1 AGTR1 ARRB1 ITSN2 LRP2 SH3GL1 ADR AP2A2(1-939) AAK1 GRB2-1 p-Y850 EPS15 SH3GL1 SYT2 AP2A2(1-939) CLTC UBB(1-76) AVPR2 PI(4)P:p-T156AP-2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinREPS1 CLTC RPS27A(1-76) DNM2 AP2S1 UBC(381-456) SNX9 SNX18 AP-2 dileucine-containing cargo CLTA AGTR1 ATP SYNJ2 SNX18 EGF CHOL SYT11 SH3KBP1 VAMP3 LDLRAP1 SNAP91 UBC(533-608) UBA52(1-76) FNBP1 FNBP1L APOB(28-4563) p-6Y-EGFR UBC(153-228) AP2A2(1-939) AGTR1 CLTB PL SH3GL3 p-Y371-CBL EGF PACSIN3 p-6Y-EGFR NAd AP2B1 UBA52(1-76) ARRB2 VAMP8 UBC(153-228) AMPH CLTC SYT11 SYT1 AVP(20-28) CLTC DNM3 CLTC EPN1 PICALM ACTR2 GTP SH3KBP1 AP2B1 TACR1 EPS15 SYT9 SNAP91 AGFG1 NECAP2 ARRB1 SH3KBP1 STAM2 UBC(609-684) ITSN2 ATP UBC(533-608) ITSN2 ITSN2 DNM2 NECAP2 AGFG1 AMPH HIP1R ARPC3 UBB(1-76) DNAJC6 ARPC3 N4GlycoAsn-PalmS WNT5A(36-380) EPN1 AVP(20-28) STON1 UBC(229-304) REPS1UBC(381-456) EPS15 CLTC AAK1 ARPC5 ARFGAP1:ARF6:GTPp-6Y-EGFR ARPC3 PACSIN1 cholesterol esters NAd SYT2 CLTC UBC(305-380) STAM SYT9 ARRB1 VAMP2 PACSIN3 DNM1 VAMP7 PI(4,5)P2:p-T156AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTP:SYNJsUBA52(1-76) UBB(153-228) N-WASP NECAP1 STON1 ARPC3 SYT9 DNM3 CLTCL1 SH3GL2 pS-ADRB2 UBC(153-228) PI(4,5)P2 UBC(1-76) LRP2 ACTR2 SYT11 SGIP1 PI4P pS-ADRB2 AP2S1 EPN1 DAB2 AP2A2(1-939) GRB2-1 SH3GL1 GAPVD1 VAMP7 PI4P SNAP91 cholesterol esters AP2A1 clathrin triskelionSYT8 UBA52(1-76) AP2B1 p-Y850 EPS15 HIP1 UBC(77-152) UBC(381-456) AMPH SH3GL2 FNBP1L f-actin EGF cholesterol esters UBC(305-380) UBC(457-532) CHOL CLTB SYT2 CLTC UBC(381-456) UBA52(1-76) SNX18 p-DVL2 f-actin AP2A2(1-939) TAGs p-Y371-CBL UBC(153-228) SYT9 FNBP1L UBB(77-152) ATP SNX18 AGFG1 EPS15L1 FNBP1 UBB(77-152) REPS1 AP2S1 UBC(77-152) AMPH HGS ACTR2 PICALM UBC(533-608) PACSIN2 NECAP1 CHRM2 N-WASP ARPC4 SNX9 SH3GL3 TACR1 p-Y371-CBL UBC(1-76) PACSIN1 UBB(1-76) ARPC2 SYT11 N-WASP PI(4)P:p-T156AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJsNAd ADR SYT8 EPN2 SYT1 NECAP1 DNAJC6 GDP PI(4,5)P2:AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1UBC(77-152) SNX9 p-Y371-CBL UBC(77-152) CLTCL1 p-T156 AP2M1 SGIP1 AP2B1 UBC(533-608) EPN1 CTTN TRIP10 AAK1 UBC(457-532) p-T156 AP2M1 VAMP7 f-actin ARPC1A SYNJ1 LDLR PIK3C2A RPS27A(1-76) DNM2 AGFG1 p-Y371-CBL AP-2 YXXPhi cargo SYT11 UBC(1-76) DNM3 ITSN1 GRB2-1 SH3GL1 LDLR AP2M1 UBC(457-532) AAK1 PACSIN2 LRP2 SYT8 TRIP10 STON2 UBC(609-684) HIP1R PiVAMP2 ITSN1 STON1 LDLR UBC(153-228) SYT11 AP2M1 PICALM NECAP2 EPS15L1 HGS ITSN2 SYNJ2 OCRL DNM2 PACSIN2 VAMP3 VAMP8 SH3GL1 ACTR3 PICALM ADPp-Y850 EPS15 DNM:GTPSNX18 GTP EGF ACTR2 UBC(609-684) DAB2 CLTB DNM1 STAM PI(4,5)P2 CLTCL1 REPS1 AP-2 dileucine-containing cargo GTP p-T156 AP2M1 EPN2 SH3GL1 ITSN1 AP2A1 ITSN2 AGTR1 f-actin AP2S1 CLTA UBC(381-456) EPS15 STAM ARPC4 FZD4 DNM1 RPS27A(1-76) UBC(609-684) SH3GL1 ARPC3 UBC(533-608) SH3GL3 ARRB2 STAM2 AGFG1 CHRM2 NECAP2 N4GlycoAsn-PalmS WNT5A(36-380) AVPR2 LRP2 CLTA GDP VAMP2 SH3KBP1 FZD4 UBB(1-76) AP2M1 PI(4,5)P2 UBC(305-380) TACR1 AAK1 Pip-T156 AP2M1 AP2M1 AMPH NAd UBC(457-532) UBC(305-380) PI(4,5)P2:p-T156AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTPSTAM2 N-WASP GGC-RAB5A UBC(1-76) AP2S1 EPN2 FZD4 ITSN2 SYT11 CTTN AP2B1 REPS2 SH3GL2 EPN2 AP-2 ComplexSYT1 DNM3 AGFG1 DAB2 AP-2 YXXPhi cargo HGS AP-2 YXXPhi cargo SH3GL1 UBB(153-228) AP2B1 ITSN1 PiSYT11 CLTC ACTR2 UBB(1-76) SYT1 CHRM2 p-6Y-EGFR SNX9 UBC(457-532) FCHO2 GAK FNBP1L ARPC4 SH3GL1 SGIP1 UBB(77-152) NECAP2 GAPVD1 PI(4)P:p-T156AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinCLTA GGC-RAB5:GDP:GAPVD1EPN2 p-DVL2 ARRB2 EPN2 ARRB1 SYNJ1 AP2A2(1-939) TRIP10 UBA52(1-76) NECAPsRPS27A(1-76) UBB(77-152) BIN1 REPS2 UBC(153-228) SGIP1 UBC(77-152) CLTC GGC-RAB5C DNM1 GDP UBC(77-152) N-WASP PL N4GlycoAsn-PalmS WNT5A(36-380) NECAP2 p-Y850 EPS15 SGIP1 HIP1 SYNJ1 HSPA8 UBB(153-228) DNM2 UBC(609-684) TACR1 ITSNscholesterol esters EGF clathrin:HSPA8:ADPpS-ADRB2 CLTA REPS1 HGS ARPC2 AP-2 YXXPhi cargo TACR1 ADR AP-2 YXXPhi cargo LDLR CLTA PL AP2A1 ACTR2 SH3KBP1 SGIP1 FZD4 UBC(609-684) DAB2 SH3KBP1 UBC(77-152) AP-2 YXXPhi cargo AVP(20-28) AP2A2(1-939) SYT2 PI(4,5)P2 SYT9 AP2A1 NAd PACSIN2 ARRB2 AP2M1 EPN2 GAK AP2S1 N4GlycoAsn-PalmS WNT5A(36-380) ARRB1 ARPC2 CHOL SNX9 AP2A1 AP2B1 SGIP1 LRP2 UBC(533-608) SH3GL2 CHOL BIN1 p-Y371-CBL STON1 GTP FZD4 AP2M1 PI(4,5)P2:p-T156AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:PIK3C2AVAMP3 BIN1 CLTB ARPC3 PACSIN1 AP2A2(1-939) EPN1 HGS AP2A2(1-939) AGFG1 UBC(153-228) LDLRAP1 TAGs PI4P VAMP2 SYT2 SYT8 CHOL cholesterol esters CTTN FCHO1 SYT11 SYT1 UBA52(1-76) OCRL AP-2 dileucine-containing cargo AP2A2(1-939) AP2A1 AP2A1 EPN1 AP2B1 AP-2 YXXPhi cargo ARPC1A AP2M1 ARPC5 APOB(28-4563) ITSN2 DNAJC6 SYT9 FNBP1 HIP1R SGIP1 GRB2-1 CLTA PI(4,5)P2LRP2 ITSN1 VAMP3 STON2 UBC(457-532) cholesterol esters SNAP91 FCHO1 p-6Y-EGFR LDLRAP1 p-AVPR2 APOB(28-4563) SH3KBP1 ITSN1 ARPC2 AVP(20-28) EPS15L1 AVPR2 p-6Y-EGFR ADR AP-2 dileucine-containing cargo N4GlycoAsn-PalmS WNT5A(36-380) p-DVL2 EPS15L1 UBC(153-228) 21, 85, 117, 123, 128...35, 57, 69, 89, 13635, 57, 69, 89, 13635, 57, 69, 89, 13621, 85, 117, 123, 128...21, 85, 117, 123, 128...21, 85, 117, 123, 128...110, 15321, 85, 117, 123, 128...7, 11, 27, 55, 91...21, 85, 117, 123, 128...35, 57, 69, 89, 13621, 85, 117, 123, 128...35, 57, 69, 89, 13621, 85, 117, 123, 128...35, 57, 69, 89, 13621, 85, 117, 123, 128...21, 85, 117, 123, 128...21, 85, 117, 123, 128...21, 85, 117, 123, 128...35, 57, 69, 89, 13635, 57, 69, 89, 13635, 57, 69, 89, 13635, 57, 69, 89, 13621, 85, 117, 123, 128...35, 57, 69, 89, 13621, 85, 117, 123, 128...35, 57, 69, 89, 13635, 57, 69, 89, 13621, 85, 117, 123, 128...35, 57, 69, 89, 13635, 57, 69, 89, 136


Description

Clathrin-mediated endocytosis (CME) is one of a number of process that control the uptake of material from the plasma membrane, and leads to the formation of clathrin-coated vesicles (Pearse et al, 1975; reviewed in Robinson, 2015; McMahon and Boucrot, 2011; Kirchhausen et al, 2014). CME contributes to signal transduction by regulating the cell surface expression and signaling of receptor tyrosine kinases (RTKs) and G-protein coupled receptors (GPCRs). Most RTKs exhibit a robust increase in internalization rate after binding specific ligands; however, some RTKs may also exhibit significant ligand-independent internalization (reviewed in Goh and Sorkin, 2013). CME controls RTK and GPCR signaling by organizing signaling both within the plasma membrane and on endosomes (reviewed in Eichel et al, 2016; Garay et al, 2015; Vieira et al, 1996; Sorkin and von Zastrow, 2014; Di Fiori and von Zastrow, 2014; Barbieri et al, 2016). CME also contributes to the uptake of material such as metabolites, hormones and other proteins from the extracellular space, and regulates membrane composition by recycling membrane components and/or targeting them for degradation.


Clathrin-mediated endocytosis involves initiation of clathrin-coated pit (CCP) formation, cargo selection, coat assembly and stabilization, membrane scission and vesicle uncoating. Although for simplicity in this pathway, the steps leading to a mature CCP are represented in a linear and temporally distinct fashion, the formation of a clathrin-coated vesicle is a highly heterogeneous process and clear temporal boundaries between these processes may not exist (see for instance Taylor et al, 2011; Antonescu et al, 2011; reviewed in Kirchhausen et al, 2014). Cargo selection in particular is a critical aspect of the formation of a mature and stable CCP, and many of the proteins involved in the initiation and maturation of a CCP contribute to cargo selection and are themselves stabilized upon incorporation of cargo into the nascent vesicle (reviewed in Kirchhausen et al, 2014; McMahon and Boucrot, 2011).



Although the clathrin triskelion was identified early as a major component of the coated vesicles, clathrin does not bind directly to membranes or to the endocytosed cargo. Vesicle formation instead relies on many proteins and adaptors that can bind the plasma membrane and interact with cargo molecules. Cargo selection depends on the recognition of endocytic signals in cytoplasmic tails of the cargo proteins by adaptors that interact with components of the vesicle's inner coat. The classic adaptor for clathrin-coated vesicles is the tetrameric AP-2 complex, which along with clathrin was identified early as a major component of the coat. Some cargo indeed bind directly to AP-2, but subsequent work has revealed a large family of proteins collectively known as CLASPs (clathrin- associated sorting proteins) that mediate the recruitment of diverse cargo into the emerging clathrin-coated vesicles (reviewed in Traub and Bonifacino, 2013). Many of these CLASP proteins themselves interact with AP-2 and clathrin, coordinating cargo recruitment with coat formation (Schmid et al, 2006; Edeling et al, 2006; reviewed in Traub and Bonifacino, 2013; Kirchhausen et al, 2014).


Initiation of CCP formation is also influenced by lipid composition, regulated by clathrin-associated phosphatases and kinases (reviewed in Picas et al, 2016). The plasma membrane is enriched in PI(4,5)P2. Many of the proteins involved in initiating clathrin-coated pit formation bind to PI(4,5)P2 and induce membrane curvature through their BAR domains (reviewed in McMahon and Boucrot, 2011; Daumke et al, 2014). Epsin also contributes to early membrane curvature through its Epsin N-terminal homology (ENTH) domain, which promotes membrane curvature by inserting into the lipid bilayer (Ford et al, 2002).

Following initiation, some CCPs progress to formation of vesicles, while others undergo disassembly at the cell surface without producing vesicles (Ehrlich et al, 2004; Loerke et al, 2009; Loerke et al, 2011; Aguet et al, 2013; Taylor et al, 2011). The assembly and stabilization of nascent CCPs is regulated by several proteins and lipids (Mettlen et al, 2009; Antonescu et al, 2011).


Maturation of the emerging clathrin-coated vesicle is accompanied by further changes in the lipid composition of the membrane and increased membrane curvature, promoted by the recruitment of N-BAR domain containing proteins (reviewed in Daumke et al, 2014; Ferguson and De Camilli, 2012; Picas et al, 2016). Some N-BAR domain containing proteins also contribute to the recruitment of the large GTPase dynamin, which is responsible for scission of the mature vesicle from the plasma membrane (Koh et al, 2007; Lundmark and Carlsson, 2003; Soulet et al, 2005; David et al, 1996; Owen et al, 1998; Shupliakov et al, 1997; Taylor et al, 2011; Ferguson et al, 2009; Aguet et al, 2013; Posor et al, 2013; Chappie et al, 2010; Shnyrova et al, 2013; reviewed in Mettlen et al, 2009; Daumke et al, 2014). After vesicle scission, the clathrin coat is dissociated from the new vesicle by the ATPase HSPA8 (also known as HSC70) and its DNAJ cofactor auxilin, priming the vesicle for fusion with a subsequent endocytic compartment and releasing clathrin for reuse (reviewed in McMahon and Boucrot, 2011; Sousa and Laufer, 2015). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8856828
Reactome-version 
Reactome version: 62
Reactome Author 
Reactome Author: Rothfels, Karen

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Bibliography

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  72. Jadot M, Canfield WM, Gregory W, Kornfeld S.; ''Characterization of the signal for rapid internalization of the bovine mannose 6-phosphate/insulin-like growth factor-II receptor.''; PubMed Europe PMC Scholia
  73. Henne WM, Kent HM, Ford MG, Hegde BG, Daumke O, Butler PJ, Mittal R, Langen R, Evans PR, McMahon HT.; ''Structure and analysis of FCHo2 F-BAR domain: a dimerizing and membrane recruitment module that effects membrane curvature.''; PubMed Europe PMC Scholia
  74. Mao Y, Balkin DM, Zoncu R, Erdmann KS, Tomasini L, Hu F, Jin MM, Hodsdon ME, De Camilli P.; ''A PH domain within OCRL bridges clathrin-mediated membrane trafficking to phosphoinositide metabolism.''; PubMed Europe PMC Scholia
  75. Gaidarov I, Zhao Y, Keen JH.; ''Individual phosphoinositide 3-kinase C2alpha domain activities independently regulate clathrin function.''; PubMed Europe PMC Scholia
  76. Wilbur JD, Chen CY, Manalo V, Hwang PK, Fletterick RJ, Brodsky FM.; ''Actin binding by Hip1 (huntingtin-interacting protein 1) and Hip1R (Hip1-related protein) is regulated by clathrin light chain.''; PubMed Europe PMC Scholia
  77. Billcliff PG, Lowe M.; ''Inositol lipid phosphatases in membrane trafficking and human disease.''; PubMed Europe PMC Scholia
  78. Sato M, Sato K, Fonarev P, Huang CJ, Liou W, Grant BD.; ''Caenorhabditis elegans RME-6 is a novel regulator of RAB-5 at the clathrin-coated pit.''; PubMed Europe PMC Scholia
  79. Schmid EM, Ford MG, Burtey A, Praefcke GJ, Peak-Chew SY, Mills IG, Benmerah A, McMahon HT.; ''Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly.''; PubMed Europe PMC Scholia
  80. Keyel PA, Mishra SK, Roth R, Heuser JE, Watkins SC, Traub LM.; ''A single common portal for clathrin-mediated endocytosis of distinct cargo governed by cargo-selective adaptors.''; PubMed Europe PMC Scholia
  81. Garay C, Judge G, Lucarelli S, Bautista S, Pandey R, Singh T, Antonescu CN.; ''Epidermal growth factor-stimulated Akt phosphorylation requires clathrin or ErbB2 but not receptor endocytosis.''; PubMed Europe PMC Scholia
  82. Lundmark R, Carlsson SR.; ''SNX9 - a prelude to vesicle release.''; PubMed Europe PMC Scholia
  83. Taylor MJ, Perrais D, Merrifield CJ.; ''A high precision survey of the molecular dynamics of mammalian clathrin-mediated endocytosis.''; PubMed Europe PMC Scholia
  84. Motley A, Bright NA, Seaman MN, Robinson MS.; ''Clathrin-mediated endocytosis in AP-2-depleted cells.''; PubMed Europe PMC Scholia
  85. Mettlen M, Stoeber M, Loerke D, Antonescu CN, Danuser G, Schmid SL.; ''Endocytic accessory proteins are functionally distinguished by their differential effects on the maturation of clathrin-coated pits.''; PubMed Europe PMC Scholia
  86. Cocucci E, Aguet F, Boulant S, Kirchhausen T.; ''The first five seconds in the life of a clathrin-coated pit.''; PubMed Europe PMC Scholia
  87. Gaidarov I, Smith ME, Domin J, Keen JH.; ''The class II phosphoinositide 3-kinase C2alpha is activated by clathrin and regulates clathrin-mediated membrane trafficking.''; PubMed Europe PMC Scholia
  88. Ford MG, Mills IG, Peter BJ, Vallis Y, Praefcke GJ, Evans PR, McMahon HT.; ''Curvature of clathrin-coated pits driven by epsin.''; PubMed Europe PMC Scholia
  89. Ehrlich M, Boll W, Van Oijen A, Hariharan R, Chandran K, Nibert ML, Kirchhausen T.; ''Endocytosis by random initiation and stabilization of clathrin-coated pits.''; PubMed Europe PMC Scholia
  90. Loerke D, Mettlen M, Schmid SL, Danuser G.; ''Measuring the hierarchy of molecular events during clathrin-mediated endocytosis.''; PubMed Europe PMC Scholia
  91. Xing Y, Böcking T, Wolf M, Grigorieff N, Kirchhausen T, Harrison SC.; ''Structure of clathrin coat with bound Hsc70 and auxilin: mechanism of Hsc70-facilitated disassembly.''; PubMed Europe PMC Scholia
  92. Waelter S, Scherzinger E, Hasenbank R, Nordhoff E, Lurz R, Goehler H, Gauss C, Sathasivam K, Bates GP, Lehrach H, Wanker EE.; ''The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis.''; PubMed Europe PMC Scholia
  93. Krauss M, Kinuta M, Wenk MR, De Camilli P, Takei K, Haucke V.; ''ARF6 stimulates clathrin/AP-2 recruitment to synaptic membranes by activating phosphatidylinositol phosphate kinase type Igamma.''; PubMed Europe PMC Scholia
  94. Cremona O, Di Paolo G, Wenk MR, Lüthi A, Kim WT, Takei K, Daniell L, Nemoto Y, Shears SB, Flavell RA, McCormick DA, De Camilli P.; ''Essential role of phosphoinositide metabolism in synaptic vesicle recycling.''; PubMed Europe PMC Scholia
  95. Moravec R, Conger KK, D'Souza R, Allison AB, Casanova JE.; ''BRAG2/GEP100/IQSec1 interacts with clathrin and regulates α5β1 integrin endocytosis through activation of ADP ribosylation factor 5 (Arf5).''; PubMed Europe PMC Scholia
  96. Di Paolo G, De Camilli P.; ''Phosphoinositides in cell regulation and membrane dynamics.''; PubMed Europe PMC Scholia
  97. Umasankar PK, Sanker S, Thieman JR, Chakraborty S, Wendland B, Tsang M, Tsang M, Traub LM.; ''Distinct and separable activities of the endocytic clathrin-coat components Fcho1/2 and AP-2 in developmental patterning.''; PubMed Europe PMC Scholia
  98. Haffner C, Takei K, Chen H, Ringstad N, Hudson A, Butler MH, Salcini AE, Di Fiore PP, De Camilli P.; ''Synaptojanin 1: localization on coated endocytic intermediates in nerve terminals and interaction of its 170 kDa isoform with Eps15.''; PubMed Europe PMC Scholia
  99. Semerdjieva S, Shortt B, Maxwell E, Singh S, Fonarev P, Hansen J, Schiavo G, Grant BD, Smythe E.; ''Coordinated regulation of AP2 uncoating from clathrin-coated vesicles by rab5 and hRME-6.''; PubMed Europe PMC Scholia
  100. Soulet F, Yarar D, Leonard M, Schmid SL.; ''SNX9 regulates dynamin assembly and is required for efficient clathrin-mediated endocytosis.''; PubMed Europe PMC Scholia
  101. Reider A, Barker SL, Mishra SK, Im YJ, Maldonado-Báez L, Hurley JH, Traub LM, Wendland B.; ''Syp1 is a conserved endocytic adaptor that contains domains involved in cargo selection and membrane tubulation.''; PubMed Europe PMC Scholia
  102. Wasiak S, Legendre-Guillemin V, Puertollano R, Blondeau F, Girard M, de Heuvel E, Boismenu D, Bell AW, Bonifacino JS, McPherson PS.; ''Enthoprotin: a novel clathrin-associated protein identified through subcellular proteomics.''; PubMed Europe PMC Scholia
  103. Yoshida Y, Kinuta M, Abe T, Liang S, Araki K, Cremona O, Di Paolo G, Moriyama Y, Yasuda T, De Camilli P, Takei K.; ''The stimulatory action of amphiphysin on dynamin function is dependent on lipid bilayer curvature.''; PubMed Europe PMC Scholia
  104. Fotin A, Cheng Y, Sliz P, Grigorieff N, Harrison SC, Kirchhausen T, Walz T.; ''Molecular model for a complete clathrin lattice from electron cryomicroscopy.''; PubMed Europe PMC Scholia
  105. Legendre-Guillemin V, Metzler M, Charbonneau M, Gan L, Chopra V, Philie J, Hayden MR, McPherson PS.; ''HIP1 and HIP12 display differential binding to F-actin, AP2, and clathrin. Identification of a novel interaction with clathrin light chain.''; PubMed Europe PMC Scholia
  106. Aguet F, Antonescu CN, Mettlen M, Schmid SL, Danuser G.; ''Advances in analysis of low signal-to-noise images link dynamin and AP2 to the functions of an endocytic checkpoint.''; PubMed Europe PMC Scholia
  107. Goh LK, Sorkin A.; ''Endocytosis of receptor tyrosine kinases.''; PubMed Europe PMC Scholia
  108. Posor Y, Eichhorn-Gruenig M, Puchkov D, Schöneberg J, Ullrich A, Lampe A, Müller R, Zarbakhsh S, Gulluni F, Hirsch E, Krauss M, Schultz C, Schmoranzer J, Noé F, Haucke V.; ''Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate.''; PubMed Europe PMC Scholia
  109. Mishra SK, Agostinelli NR, Brett TJ, Mizukami I, Ross TS, Traub LM.; ''Clathrin- and AP-2-binding sites in HIP1 uncover a general assembly role for endocytic accessory proteins.''; PubMed Europe PMC Scholia
  110. Doray B, Lee I, Knisely J, Bu G, Kornfeld S.; ''The gamma/sigma1 and alpha/sigma2 hemicomplexes of clathrin adaptors AP-1 and AP-2 harbor the dileucine recognition site.''; PubMed Europe PMC Scholia
  111. Sorkin A, von Zastrow M.; ''Endocytosis and signalling: intertwining molecular networks.''; PubMed Europe PMC Scholia
  112. Shin HW, Hayashi M, Christoforidis S, Lacas-Gervais S, Hoepfner S, Wenk MR, Modregger J, Uttenweiler-Joseph S, Wilm M, Nystuen A, Frankel WN, Solimena M, De Camilli P, Zerial M.; ''An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway.''; PubMed Europe PMC Scholia
  113. Henderson DM, Conner SD.; ''A novel AAK1 splice variant functions at multiple steps of the endocytic pathway.''; PubMed Europe PMC Scholia
  114. Mettlen M, Loerke D, Yarar D, Danuser G, Schmid SL.; ''Cargo- and adaptor-specific mechanisms regulate clathrin-mediated endocytosis.''; PubMed Europe PMC Scholia
  115. Massol RH, Boll W, Griffin AM, Kirchhausen T.; ''A burst of auxilin recruitment determines the onset of clathrin-coated vesicle uncoating.''; PubMed Europe PMC Scholia
  116. Daumke O, Roux A, Haucke V.; ''BAR domain scaffolds in dynamin-mediated membrane fission.''; PubMed Europe PMC Scholia
  117. Paleotti O, Macia E, Luton F, Klein S, Partisani M, Chardin P, Kirchhausen T, Franco M.; ''The small G-protein Arf6GTP recruits the AP-2 adaptor complex to membranes.''; PubMed Europe PMC Scholia
  118. Barbieri E, Di Fiore PP, Sigismund S.; ''Endocytic control of signaling at the plasma membrane.''; PubMed Europe PMC Scholia
  119. Loerke D, Mettlen M, Yarar D, Jaqaman K, Jaqaman H, Danuser G, Schmid SL.; ''Cargo and dynamin regulate clathrin-coated pit maturation.''; PubMed Europe PMC Scholia
  120. McMahon HT, Boucrot E.; ''Molecular mechanism and physiological functions of clathrin-mediated endocytosis.''; PubMed Europe PMC Scholia
  121. Gaidarov I, Santini F, Warren RA, Keen JH.; ''Spatial control of coated-pit dynamics in living cells.''; PubMed Europe PMC Scholia
  122. Perera RM, Zoncu R, Lucast L, De Camilli P, Toomre D.; ''Two synaptojanin 1 isoforms are recruited to clathrin-coated pits at different stages.''; PubMed Europe PMC Scholia
  123. Meinecke M, Boucrot E, Camdere G, Hon WC, Mittal R, McMahon HT.; ''Cooperative recruitment of dynamin and BIN/amphiphysin/Rvs (BAR) domain-containing proteins leads to GTP-dependent membrane scission.''; PubMed Europe PMC Scholia
  124. Chappie JS, Mears JA, Fang S, Leonard M, Schmid SL, Milligan RA, Hinshaw JE, Dyda F.; ''A pseudoatomic model of the dynamin polymer identifies a hydrolysis-dependent powerstroke.''; PubMed Europe PMC Scholia
  125. Di Fiore PP, von Zastrow M.; ''Endocytosis, signaling, and beyond.''; PubMed Europe PMC Scholia
  126. Koh TW, Korolchuk VI, Wairkar YP, Jiao W, Evergren E, Pan H, Zhou Y, Venken KJ, Shupliakov O, Robinson IM, O'Kane CJ, Bellen HJ.; ''Eps15 and Dap160 control synaptic vesicle membrane retrieval and synapse development.''; PubMed Europe PMC Scholia
  127. Christoforidis S, Miaczynska M, Ashman K, Wilm M, Zhao L, Yip SC, Waterfield MD, Backer JM, Zerial M.; ''Phosphatidylinositol-3-OH kinases are Rab5 effectors.''; PubMed Europe PMC Scholia
  128. Kirchhausen T, Owen D, Harrison SC.; ''Molecular structure, function, and dynamics of clathrin-mediated membrane traffic.''; PubMed Europe PMC Scholia
  129. Neumann S, Schmid SL.; ''Dual role of BAR domain-containing proteins in regulating vesicle release catalyzed by the GTPase, dynamin-2.''; PubMed Europe PMC Scholia
  130. Taylor MJ, Lampe M, Merrifield CJ.; ''A feedback loop between dynamin and actin recruitment during clathrin-mediated endocytosis.''; PubMed Europe PMC Scholia
  131. Ferguson SM, Raimondi A, Paradise S, Shen H, Mesaki K, Ferguson A, Destaing O, Ko G, Takasaki J, Cremona O, O' Toole E, De Camilli P.; ''Coordinated actions of actin and BAR proteins upstream of dynamin at endocytic clathrin-coated pits.''; PubMed Europe PMC Scholia
  132. Sweitzer SM, Hinshaw JE.; ''Dynamin undergoes a GTP-dependent conformational change causing vesiculation.''; PubMed Europe PMC Scholia
  133. Takei K, Slepnev VI, Haucke V, De Camilli P.; ''Functional partnership between amphiphysin and dynamin in clathrin-mediated endocytosis.''; PubMed Europe PMC Scholia
  134. Ferguson SM, De Camilli P.; ''Dynamin, a membrane-remodelling GTPase.''; PubMed Europe PMC Scholia
  135. Bairstow SF, Ling K, Su X, Firestone AJ, Carbonara C, Anderson RA.; ''Type Igamma661 phosphatidylinositol phosphate kinase directly interacts with AP2 and regulates endocytosis.''; PubMed Europe PMC Scholia
  136. Vieira AV, Lamaze C, Schmid SL.; ''Control of EGF receptor signaling by clathrin-mediated endocytosis.''; PubMed Europe PMC Scholia
  137. Traub LM, Bonifacino JS.; ''Cargo recognition in clathrin-mediated endocytosis.''; PubMed Europe PMC Scholia
  138. Dittman J, Ryan TA.; ''Molecular circuitry of endocytosis at nerve terminals.''; PubMed Europe PMC Scholia
  139. Ungewickell E, Ungewickell H, Holstein SE, Lindner R, Prasad K, Barouch W, Martin B, Greene LE, Eisenberg E.; ''Role of auxilin in uncoating clathrin-coated vesicles.''; PubMed Europe PMC Scholia
  140. Mettlen M, Pucadyil T, Ramachandran R, Schmid SL.; ''Dissecting dynamin's role in clathrin-mediated endocytosis.''; PubMed Europe PMC Scholia
  141. Marie B, Sweeney ST, Poskanzer KE, Roos J, Kelly RB, Davis GW.; ''Dap160/intersectin scaffolds the periactive zone to achieve high-fidelity endocytosis and normal synaptic growth.''; PubMed Europe PMC Scholia
  142. Puthenveedu MA, von Zastrow M.; ''Cargo regulates clathrin-coated pit dynamics.''; PubMed Europe PMC Scholia
  143. Antonescu CN, Aguet F, Danuser G, Schmid SL.; ''Phosphatidylinositol-(4,5)-bisphosphate regulates clathrin-coated pit initiation, stabilization, and size.''; PubMed Europe PMC Scholia
  144. Storch S, Braulke T.; ''Multiple C-terminal motifs of the 46-kDa mannose 6-phosphate receptor tail contribute to efficient binding of medium chains of AP-2 and AP-3.''; PubMed Europe PMC Scholia
  145. Traub LM.; ''Tickets to ride: selecting cargo for clathrin-regulated internalization.''; PubMed Europe PMC Scholia
  146. Ogata S, Fukuda M.; ''Lysosomal targeting of Limp II membrane glycoprotein requires a novel Leu-Ile motif at a particular position in its cytoplasmic tail.''; PubMed Europe PMC Scholia
  147. Erdmann KS, Mao Y, McCrea HJ, Zoncu R, Lee S, Paradise S, Modregger J, Biemesderfer D, Toomre D, De Camilli P.; ''A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway.''; PubMed Europe PMC Scholia
  148. Conner SD, Schmid SL.; ''Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis.''; PubMed Europe PMC Scholia
  149. Domin J, Gaidarov I, Smith ME, Keen JH, Waterfield MD.; ''The class II phosphoinositide 3-kinase PI3K-C2alpha is concentrated in the trans-Golgi network and present in clathrin-coated vesicles.''; PubMed Europe PMC Scholia
  150. Kim MH, Hersh LB.; ''The vesicular acetylcholine transporter interacts with clathrin-associated adaptor complexes AP-1 and AP-2.''; PubMed Europe PMC Scholia
  151. Kamioka Y, Fukuhara S, Sawa H, Nagashima K, Masuda M, Matsuda M, Mochizuki N.; ''A novel dynamin-associating molecule, formin-binding protein 17, induces tubular membrane invaginations and participates in endocytosis.''; PubMed Europe PMC Scholia
  152. Pearse BM.; ''Coated vesicles from pig brain: purification and biochemical characterization.''; PubMed Europe PMC Scholia
  153. Owen DJ, Evans PR.; ''A structural explanation for the recognition of tyrosine-based endocytotic signals.''; PubMed Europe PMC Scholia
  154. Hinshaw JE, Schmid SL.; ''Dynamin self-assembles into rings suggesting a mechanism for coated vesicle budding.''; PubMed Europe PMC Scholia
  155. Olusanya O, Andrews PD, Swedlow JR, Smythe E.; ''Phosphorylation of threonine 156 of the mu2 subunit of the AP2 complex is essential for endocytosis in vitro and in vivo.''; PubMed Europe PMC Scholia
  156. Gu M, Liu Q, Watanabe S, Sun L, Hollopeter G, Grant BD, Jorgensen EM.; ''AP2 hemicomplexes contribute independently to synaptic vesicle endocytosis.''; PubMed Europe PMC Scholia
  157. Krauss M, Kukhtina V, Pechstein A, Haucke V.; ''Stimulation of phosphatidylinositol kinase type I-mediated phosphatidylinositol (4,5)-bisphosphate synthesis by AP-2mu-cargo complexes.''; PubMed Europe PMC Scholia
  158. Shimada A, Niwa H, Tsujita K, Suetsugu S, Nitta K, Hanawa-Suetsugu K, Akasaka R, Nishino Y, Toyama M, Chen L, Liu ZJ, Wang BC, Yamamoto M, Terada T, Miyazawa A, Tanaka A, Sugano S, Shirouzu M, Nagayama K, Takenawa T, Yokoyama S.; ''Curved EFC/F-BAR-domain dimers are joined end to end into a filament for membrane invagination in endocytosis.''; PubMed Europe PMC Scholia
  159. Cestra G, Castagnoli L, Dente L, Minenkova O, Petrelli A, Migone N, Hoffmüller U, Schneider-Mergener J, Cesareni G.; ''The SH3 domains of endophilin and amphiphysin bind to the proline-rich region of synaptojanin 1 at distinct sites that display an unconventional binding specificity.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
115077view17:02, 25 January 2021ReactomeTeamReactome version 75
113559view13:13, 2 November 2020DeSlOntology Term : 'regulatory pathway' added !
113558view13:12, 2 November 2020DeSlOntology Term : 'clathrin-mediated endocytosis pathway' added !
113519view11:59, 2 November 2020ReactomeTeamReactome version 74
112718view16:12, 9 October 2020ReactomeTeamReactome version 73
101634view11:49, 1 November 2018ReactomeTeamreactome version 66
101170view21:36, 31 October 2018ReactomeTeamreactome version 65
100696view20:09, 31 October 2018ReactomeTeamreactome version 64
100246view16:54, 31 October 2018ReactomeTeamreactome version 63
99798view15:19, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99348view12:48, 31 October 2018ReactomeTeamreactome version 62
93371view11:21, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AAK1 ProteinQ2M2I8 (Uniprot-TrEMBL)
AAK1ProteinQ2M2I8 (Uniprot-TrEMBL)
ACTR2 ProteinP61160 (Uniprot-TrEMBL)
ACTR3 ProteinP61158 (Uniprot-TrEMBL)
ADP MetaboliteCHEBI:16761 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
ADR MetaboliteCHEBI:28918 (ChEBI)
AGFG1 ProteinP52594 (Uniprot-TrEMBL)
AGTR1 ProteinP30556 (Uniprot-TrEMBL)
AMPH ProteinP49418 (Uniprot-TrEMBL)
AMPH:BIN1ComplexR-HSA-8868606 (Reactome)
AP-2 ComplexComplexR-HSA-167712 (Reactome)
AP-2 YXXPhi cargo R-HSA-8866232 (Reactome)
AP-2 YXXPhi cargo R-HSA-8869159 (Reactome)
AP-2 dileucine-containing cargo R-HSA-8866234 (Reactome)
AP-2 dileucine-containing cargo R-HSA-8869156 (Reactome)
AP2A1 ProteinO95782 (Uniprot-TrEMBL)
AP2A2(1-939) ProteinO94973 (Uniprot-TrEMBL)
AP2B1 ProteinP63010 (Uniprot-TrEMBL)
AP2M1 ProteinQ96CW1 (Uniprot-TrEMBL)
AP2S1 ProteinP53680 (Uniprot-TrEMBL)
APOB(28-4563) ProteinP04114 (Uniprot-TrEMBL)
ARF6 ProteinP62330 (Uniprot-TrEMBL)
ARFGAP1 ProteinQ8N6T3 (Uniprot-TrEMBL)
ARFGAP1:ARF6:GTPComplexR-HSA-8871133 (Reactome)
ARP2/3 complexComplexR-HSA-8868713 (Reactome)
ARPC1A ProteinQ92747 (Uniprot-TrEMBL)
ARPC2 ProteinO15144 (Uniprot-TrEMBL)
ARPC3 ProteinO15145 (Uniprot-TrEMBL)
ARPC4 ProteinP59998 (Uniprot-TrEMBL)
ARPC5 ProteinO15511 (Uniprot-TrEMBL)
ARRB1 ProteinP49407 (Uniprot-TrEMBL)
ARRB2 ProteinP32121 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
AVP(20-28) ProteinP01185 (Uniprot-TrEMBL)
AVPR2 ProteinP30518 (Uniprot-TrEMBL)
BIN1 ProteinO00499 (Uniprot-TrEMBL)
CHOL MetaboliteCHEBI:16113 (ChEBI)
CHRM2 ProteinP08172 (Uniprot-TrEMBL)
CLASP proteins:cargoComplexR-HSA-8867603 (Reactome)
CLASP proteins:cargoComplexR-HSA-8868710 (Reactome)
CLTA ProteinP09496 (Uniprot-TrEMBL)
CLTB ProteinP09497 (Uniprot-TrEMBL)
CLTC ProteinQ00610 (Uniprot-TrEMBL)
CLTCL1 ProteinP53675 (Uniprot-TrEMBL)
CTTN ProteinQ14247 (Uniprot-TrEMBL)
Cargo recognition

for clathrin-mediated

endocytosis
PathwayR-HSA-8856825 (Reactome) Recruitment of plasma membrane-localized cargo into clathrin-coated endocytic vesicles is mediated by interaction with a variety of clathrin-interacting proteins collectively called CLASPs (clathrin-associated sorting proteins). CLASP proteins, which may be monomeric or tetrameric, are recruited to the plasma membrane through interaction with phosphoinsitides and recognize linear or conformational sequences or post-translational modifications in the cytoplasmic tails of the cargo protein. Through bivalent interactions with clathrin and/or other CLASP proteins, they bridge the recruitment of the cargo to the emerging clathrin coated pit (reviewed in Traub and Bonifacino, 2013). The tetrameric AP-2 complex, first identified in early studies of clathrin-mediated endocytosis, was at one time thought to be the primary CLASP protein involved in cargo recognition at the plasma membrane, and indeed plays a key role in the endocytosis of cargo carrying dileucine- or tyrosine-based motifs.

A number of studies have been performed to test whether AP-2 is essential for all forms of clathrin-mediated endocytosis (Keyel et al, 2006; Motely et al, 2003; Huang et al, 2004; Boucrot et al, 2010; Henne et al, 2010; Johannessen et al, 2006; Gu et al, 2013; reviewed in Traub, 2009; McMahon and Boucrot, 2011). Although depletion of AP-2 differentially affects the endocytosis of different cargo, extensive depletion of AP-2 through RNAi reduces clathrin-coated pit formation by 80-90%, and the CCPs that do form still contain AP-2, highlighting the critcical role of this complex in CME (Johannessen et al, 2006; Boucrot et al, 2010; Henne et al, 2010).


In addition to AP-2, a wide range of other CLASPs including proteins of the beta-arrestin, stonin and epsin families, engage sorting motifs in other cargo and interact either with clathrin, AP-2 or each other to facilitate assembly of a clathin-coated pit (reviewed in Traub and Bonifacino, 2013).
DAB2 ProteinP98082 (Uniprot-TrEMBL)
DNAJC6 ProteinO75061 (Uniprot-TrEMBL)
DNM1 ProteinQ05193 (Uniprot-TrEMBL)
DNM2 ProteinP50570 (Uniprot-TrEMBL)
DNM3 ProteinQ9UQ16 (Uniprot-TrEMBL)
DNM:GDPComplexR-HSA-8868609 (Reactome)
DNM:GTPComplexR-HSA-8868235 (Reactome)
EGF ProteinP01133 (Uniprot-TrEMBL)
EPN1 ProteinQ9Y6I3 (Uniprot-TrEMBL)
EPN2 ProteinO95208 (Uniprot-TrEMBL)
EPS15 ProteinP42566 (Uniprot-TrEMBL)
EPS15L1 ProteinQ9UBC2 (Uniprot-TrEMBL)
EPS15ProteinP42566 (Uniprot-TrEMBL)
FCHO1 ProteinO14526 (Uniprot-TrEMBL)
FCHO1,2 dimerComplexR-HSA-8862270 (Reactome)
FCHO2 ProteinQ0JRZ9 (Uniprot-TrEMBL)
FNBP1 ProteinQ96RU3 (Uniprot-TrEMBL)
FNBP1 dimerComplexR-HSA-8868046 (Reactome)
FNBP1L ProteinQ5T0N5 (Uniprot-TrEMBL)
FNBP1L dimerComplexR-HSA-8868045 (Reactome)
FZD4 ProteinQ9ULV1 (Uniprot-TrEMBL)
GAK ProteinO14976 (Uniprot-TrEMBL)
GAK,DNAJC6ComplexR-HSA-8868618 (Reactome)
GAPVD1 ProteinQ14C86 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GGC-RAB5:GDP:GAPVD1ComplexR-HSA-8871139 (Reactome)
GGC-RAB5:GTP:GAPVD1ComplexR-HSA-8871142 (Reactome)
GGC-RAB5A ProteinP20339 (Uniprot-TrEMBL)
GGC-RAB5B ProteinP61020 (Uniprot-TrEMBL)
GGC-RAB5C ProteinP51148 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HGS ProteinO14964 (Uniprot-TrEMBL)
HIP1 ProteinO00291 (Uniprot-TrEMBL)
HIP1 dimerComplexR-HSA-8868219 (Reactome)
HIP1R ProteinO75146 (Uniprot-TrEMBL)
HIP1R dimerComplexR-HSA-8868221 (Reactome)
HSPA8 ProteinP11142 (Uniprot-TrEMBL)
HSPA8:ATPComplexR-HSA-5251937 (Reactome)
ITSN1 ProteinQ15811 (Uniprot-TrEMBL)
ITSN2 ProteinQ9NZM3 (Uniprot-TrEMBL)
ITSNsComplexR-HSA-8862274 (Reactome)
LDLR ProteinP01130 (Uniprot-TrEMBL)
LDLRAP1 ProteinQ5SW96 (Uniprot-TrEMBL)
LRP2 ProteinP98164 (Uniprot-TrEMBL)
N-WASP ProteinO00401 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT5A(36-380) ProteinP41221 (Uniprot-TrEMBL)
NAd MetaboliteCHEBI:18357 (ChEBI)
NECAP1 ProteinQ8NC96 (Uniprot-TrEMBL)
NECAP2 ProteinQ9NVZ3 (Uniprot-TrEMBL)
NECAPsComplexR-HSA-8863469 (Reactome)
OCRL ProteinQ01968 (Uniprot-TrEMBL)
PACSIN dimersComplexR-HSA-8868621 (Reactome)
PACSIN1 ProteinQ9BY11 (Uniprot-TrEMBL)
PACSIN2 ProteinQ9UNF0 (Uniprot-TrEMBL)
PACSIN3 ProteinQ9UKS6 (Uniprot-TrEMBL)
PI(3,4)P2MetaboliteCHEBI:16152 (ChEBI)
PI(4)P:p-T156 AP-2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinComplexR-HSA-8868620 (Reactome)
PI(4)P:p-T156 AP-2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinComplexR-HSA-8871149 (Reactome)
PI(4)P:p-T156 AP-2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinGGC-RAB5:GTP:GAPVD1ComplexR-HSA-8871150 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilin:HSPA8:ATPComplexR-HSA-8868627 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinComplexR-HSA-8868626 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJsComplexR-HSA-8868624 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTP:SYNJsComplexR-HSA-8868629 (Reactome)
PI(4,5)P2 MetaboliteCHEBI:18348 (ChEBI)
PI(4,5)P2:AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1ComplexR-HSA-8868048 (Reactome)
PI(4,5)P2:AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1ComplexR-HSA-8862276 (Reactome)
PI(4,5)P2:AP-2:clathrinComplexR-HSA-8871153 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:PIK3C2AComplexR-HSA-8868051 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargoComplexR-HSA-8867753 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1ComplexR-HSA-8856806 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTP:SYNJsComplexR-HSA-8868634 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTPComplexR-HSA-8868234 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimersComplexR-HSA-8868232 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteinsComplexR-HSA-8867751 (Reactome)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI4P MetaboliteCHEBI:17526 (ChEBI)
PI4PMetaboliteCHEBI:17526 (ChEBI)
PICALM ProteinQ13492 (Uniprot-TrEMBL)
PIK3C2A ProteinO00443 (Uniprot-TrEMBL)
PIK3C2AProteinO00443 (Uniprot-TrEMBL)
PIP5K1CProteinO60331 (Uniprot-TrEMBL)
PL MetaboliteCHEBI:16247 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
REPS1 ProteinQ96D71 (Uniprot-TrEMBL)
REPS1ProteinQ96D71 (Uniprot-TrEMBL)
REPS2 ProteinQ8NFH8 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SGIP1 ProteinQ9BQI5 (Uniprot-TrEMBL)
SGIP1ProteinQ9BQI5 (Uniprot-TrEMBL)
SH3GL1 ProteinQ99961 (Uniprot-TrEMBL)
SH3GL2 ProteinQ99962 (Uniprot-TrEMBL)
SH3GL3 ProteinQ99963 (Uniprot-TrEMBL)
SH3GLsComplexR-HSA-8867746 (Reactome)
SH3KBP1 ProteinQ96B97 (Uniprot-TrEMBL)
SNAP91 ProteinO60641 (Uniprot-TrEMBL)
SNX18 ProteinQ96RF0 (Uniprot-TrEMBL)
SNX9 ProteinQ9Y5X1 (Uniprot-TrEMBL)
SNX9,18ComplexR-HSA-8868040 (Reactome)
STAM ProteinQ92783 (Uniprot-TrEMBL)
STAM2 ProteinO75886 (Uniprot-TrEMBL)
STON1 ProteinQ9Y6Q2 (Uniprot-TrEMBL)
STON2 ProteinQ8WXE9 (Uniprot-TrEMBL)
SYNJ1 ProteinO43426 (Uniprot-TrEMBL)
SYNJ2 ProteinO15056 (Uniprot-TrEMBL)
SYNJs,OCRLComplexR-HSA-1806173 (Reactome)
SYT1 ProteinP21579 (Uniprot-TrEMBL)
SYT11 ProteinQ9BT88 (Uniprot-TrEMBL)
SYT2 ProteinQ8N9I0 (Uniprot-TrEMBL)
SYT8 ProteinQ8NBV8 (Uniprot-TrEMBL)
SYT9 ProteinQ86SS6 (Uniprot-TrEMBL)
TACR1 ProteinP25103 (Uniprot-TrEMBL)
TAGs MetaboliteCHEBI:17855 (ChEBI)
TRIP10 ProteinQ15642 (Uniprot-TrEMBL)
TRIP10 dimerComplexR-HSA-8868042 (Reactome)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
VAMP2 ProteinP63027 (Uniprot-TrEMBL)
VAMP3 ProteinQ15836 (Uniprot-TrEMBL)
VAMP7 ProteinP51809 (Uniprot-TrEMBL)
VAMP8 ProteinQ9BV40 (Uniprot-TrEMBL)
WASL,CTTNComplexR-HSA-8868228 (Reactome)
cholesterol esters MetaboliteCHEBI:17002 (ChEBI)
clathrin triskelionComplexR-HSA-8856809 (Reactome)
clathrin:HSPA8:ADPComplexR-HSA-8868617 (Reactome)
f-actin R-HSA-202986 (Reactome)
f-actinR-HSA-202986 (Reactome)
p-6Y-EGFR ProteinP00533 (Uniprot-TrEMBL)
p-AVPR2 ProteinP30518 (Uniprot-TrEMBL)
p-DVL2 ProteinO14641 (Uniprot-TrEMBL)
p-T156 AP2M1 ProteinQ96CW1 (Uniprot-TrEMBL)
p-Y371-CBL ProteinP22681 (Uniprot-TrEMBL)
p-Y850 EPS15 ProteinP42566 (Uniprot-TrEMBL)
pS-ADRB2 ProteinP07550 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
AAK1ArrowR-HSA-8871193 (Reactome)
AAK1R-HSA-8856808 (Reactome)
ADPArrowR-HSA-8856813 (Reactome)
ADPArrowR-HSA-8868066 (Reactome)
ADPArrowR-HSA-8868072 (Reactome)
AMPH:BIN1ArrowR-HSA-8869438 (Reactome)
AMPH:BIN1R-HSA-8867754 (Reactome)
AP-2 ComplexArrowR-HSA-8869438 (Reactome)
AP-2 ComplexR-HSA-8856808 (Reactome)
AP-2 ComplexR-HSA-8871196 (Reactome)
ARFGAP1:ARF6:GTPArrowR-HSA-8856808 (Reactome)
ARP2/3 complexArrowR-HSA-8869438 (Reactome)
ARP2/3 complexR-HSA-8868230 (Reactome)
ATPR-HSA-8856813 (Reactome)
ATPR-HSA-8868066 (Reactome)
ATPR-HSA-8868072 (Reactome)
CLASP proteins:cargoArrowR-HSA-8869438 (Reactome)
CLASP proteins:cargoR-HSA-8867756 (Reactome)
DNM:GDPArrowR-HSA-8869438 (Reactome)
DNM:GTPR-HSA-8868236 (Reactome)
EPS15ArrowR-HSA-8869438 (Reactome)
EPS15R-HSA-8862280 (Reactome)
FCHO1,2 dimerArrowR-HSA-8867754 (Reactome)
FCHO1,2 dimerR-HSA-8862280 (Reactome)
FNBP1 dimerArrowR-HSA-8869438 (Reactome)
FNBP1 dimerR-HSA-8867754 (Reactome)
FNBP1L dimerArrowR-HSA-8869438 (Reactome)
FNBP1L dimerR-HSA-8867754 (Reactome)
GAK,DNAJC6ArrowR-HSA-8869438 (Reactome)
GAK,DNAJC6R-HSA-8868659 (Reactome)
GGC-RAB5:GDP:GAPVD1R-HSA-8871194 (Reactome)
GGC-RAB5:GTP:GAPVD1ArrowR-HSA-8869438 (Reactome)
H2OR-HSA-8868648 (Reactome)
H2OR-HSA-8868658 (Reactome)
H2OR-HSA-8868661 (Reactome)
HIP1 dimerArrowR-HSA-8869438 (Reactome)
HIP1 dimerR-HSA-8868230 (Reactome)
HIP1R dimerArrowR-HSA-8869438 (Reactome)
HIP1R dimerR-HSA-8868230 (Reactome)
HSPA8:ATPR-HSA-8868660 (Reactome)
ITSNsArrowR-HSA-8869438 (Reactome)
ITSNsR-HSA-8862280 (Reactome)
NECAPsArrowR-HSA-8869438 (Reactome)
NECAPsR-HSA-8856808 (Reactome)
PACSIN dimersArrowR-HSA-8869438 (Reactome)
PACSIN dimersR-HSA-8867754 (Reactome)
PI(3,4)P2ArrowR-HSA-8867754 (Reactome)
PI(3,4)P2ArrowR-HSA-8868072 (Reactome)
PI(4)P:p-T156 AP-2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinArrowR-HSA-8868658 (Reactome)
PI(4)P:p-T156 AP-2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinArrowR-HSA-8871194 (Reactome)
PI(4)P:p-T156 AP-2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinR-HSA-8871193 (Reactome)
PI(4)P:p-T156 AP-2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinR-HSA-8871194 (Reactome)
PI(4)P:p-T156 AP-2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinGGC-RAB5:GTP:GAPVD1ArrowR-HSA-8871193 (Reactome)
PI(4)P:p-T156 AP-2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinGGC-RAB5:GTP:GAPVD1R-HSA-8869438 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilin:HSPA8:ATPArrowR-HSA-8868660 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilin:HSPA8:ATPR-HSA-8868658 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilin:HSPA8:ATPmim-catalysisR-HSA-8868658 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinArrowR-HSA-8868659 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJs:auxilinR-HSA-8868660 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJsArrowR-HSA-8868661 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GDP:SYNJsR-HSA-8868659 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTP:SYNJsArrowR-HSA-8868648 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTP:SYNJsR-HSA-8868661 (Reactome)
PI(4)P:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTP:SYNJsmim-catalysisR-HSA-8868661 (Reactome)
PI(4,5)P2:AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1ArrowR-HSA-8856808 (Reactome)
PI(4,5)P2:AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1R-HSA-8856813 (Reactome)
PI(4,5)P2:AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1mim-catalysisR-HSA-8856813 (Reactome)
PI(4,5)P2:AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1ArrowR-HSA-8862280 (Reactome)
PI(4,5)P2:AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1R-HSA-8856808 (Reactome)
PI(4,5)P2:AP-2:clathrinArrowR-HSA-8871196 (Reactome)
PI(4,5)P2:AP-2:clathrinR-HSA-8862280 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:PIK3C2AArrowR-HSA-8868071 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:PIK3C2AR-HSA-8867754 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:PIK3C2Amim-catalysisR-HSA-8868072 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargoArrowR-HSA-8867756 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargoR-HSA-8868071 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1ArrowR-HSA-8856813 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1R-HSA-8867756 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTP:SYNJsArrowR-HSA-8868651 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTP:SYNJsR-HSA-8868648 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTP:SYNJsmim-catalysisR-HSA-8868648 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTPArrowR-HSA-8868236 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimers:DNM:GTPR-HSA-8868651 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimersArrowR-HSA-8868230 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteins:ARP2/3 complex:WASL:f-actin:HIP dimersR-HSA-8868236 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteinsArrowR-HSA-8867754 (Reactome)
PI(4,5)P2:p-T156 AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteinsR-HSA-8868230 (Reactome)
PI(4,5)P2ArrowR-HSA-8868066 (Reactome)
PI(4,5)P2R-HSA-8871196 (Reactome)
PI4PArrowR-HSA-8869438 (Reactome)
PI4PR-HSA-8868066 (Reactome)
PI4PR-HSA-8868072 (Reactome)
PIK3C2AArrowR-HSA-8867754 (Reactome)
PIK3C2AR-HSA-8868071 (Reactome)
PIP5K1Cmim-catalysisR-HSA-8868066 (Reactome)
PiArrowR-HSA-8868648 (Reactome)
PiArrowR-HSA-8868658 (Reactome)
PiArrowR-HSA-8868661 (Reactome)
R-HSA-8856808 (Reactome) Recruitment of early acting proteins such as the FCHo and ITSN proteins stabilizes the transient AP-2:clathrin complex at the plasma membrane and is rapidly followed by incorporation of many more molecules of AP-2 and clathrin. AP-2 binding to the plasma-membrane enriched PI(4,5)P2 is reinforced early in the formation of a CCP by the interaction of AP-2 with PIP5K1C, which synthesizes PI(4)P to PI(4,5)P2 (Krauss et al, 2006; Bairstow et al, 2006; Thieman et al, 2009).

AP-2 recruitment is also promoted by conformational changes upon lipid and protein binding. AP-2 is a heterotetramer consisting of two large subunits (alpha and beta1 adaptin), a medium mu2 subunit and a small sigma2 subunit, and exists in a closed conformation when not part of a clathrin-coated pit (Jackson et al, 2010).
Interactions between the AP-2 mu2 subunit and PIP2 within the lipid bilayer stabilize the 'open' conformation of AP-2, exposing binding sites for cargo proteins. The open conformation is also promoted by interaction of AP-2 with early CCP proteins such as SGIP and FCHo2 (Hollopeter et al, 2014). Recruitment of clathrin stimulates the activity of AAK1, an AP-2 kinase that phosphorylates the mu2 subunit of the adaptor complex at Thr156, further stabilizing the open conformation and promoting cargo recruitment (Olusanya et al, 2001; Ricotta et al, 2002; Conner et al, 2002; Conner et al, 2003).

NECAP1 and 2 may also aid in the assembly of an emergent clathrin-coated pit. NECAP proteins have a WxxF motif at the C-terminus that binds with high affinity to the alpha-ear sandwich domain of AP-2 and an N-terminal PH ear domain that interacts both with AP-2 and a wide range of endocytic accessory proteins containing FxDxF motifs (Ritter et al, 2003; Wasiak et al, 2002; Ritter et al, 2013). Clathrin and the NECAP PH ear domain appear to compete for an AP-2 binding site. Clathrin-mediated displacement of the NECAP PH ear domain from its lower affinity AP-2 site may allow release this domain, allowing it to transition to a role in recruiting endocytic accessory proteins and cargo (Ritter et al, 2007; Ritter et al, 2013; reviewed in McMahon and Boucrot, 2011).


Finally, studies have highlighted a role for ARF6 and its GTPase activating protein ARFGAP1 in CCP formation, although the details remain to be established.
ARFGAP1 and ARF6 appear to contribute to the recruitment of some cargo, but may also play a more generalized role in CCP formation (Moravec et al, 2012; Bai et al, 2011). ARFGAP1 binds directly to AP-2 and its GAP activity is required for CME. Consistent with this, silencing of ARFGAP1 impairs CME (Schmid et al, 2006; Rawet et al 2010; Bai et al 2011). ARFGAP1 has activity towards several ARFs, including ARF6 which is found is some CCPs and is known to regulate CME under some circumstances (Moravec et al, 2003; Palacios et al, 2002; Paleotti et al, 2005; Kraus et al, 2003). ARF6 is thought to contribute to the recruitment of AP-2 and clathrin to the plasma membrane, possibly in part by affecting the lipid composition (Paleotti et al, 2002; Krauss et al, 2003).


R-HSA-8856813 (Reactome) AAK1 is a serine-threonine kinase that phosphorylates T156 of the AP2 mu2 subunit (Olusanya et al, 2001; Conner et al, 2002; Conner et al, 2003). This phosphorylation is thought to stabilize the open conformation of the AP-2 complex, exposing the cargo-binding sites and promoting cargo capture (Ricotta et al, 2002). AAK1 kinase activity is stimulated by interaction with clathrin (Conner et al, 2003; Henderson et al, 2007).
R-HSA-8862280 (Reactome) Stabilization of the transient binding of AP-2 and clathrin at the plasma membrane is effected by the recruitment of a number of early acting proteins, including FCHo (F-BAR domain-containing Fer/Cip4 homology domain-only) proteins 1 and 2, intersectins (ITSNs), EPS15, EPS15L1, REPS1 and SGIP1 among others (Henne et al, 2010; Stimpson et al, 2009; Reider et al, 2009; Dergai et al, 2010; Antonescu et al, 2011; reviewed in McMahon and Boucrot, 2011).

FCHo proteins interact with the plasma membrane-enriched PI(4,5)P2 through the F-BAR domain, which recognizes curvature in the membrane (Henne et al, 2010; Henne et al, 2007; Shimada et al, 2007; Umasankar et al, 2012). Other F-BAR proteins, such as FNBP1 and FNBP1L may join the nascent clathrin-coated pit at a slightly later stage (Shimada et al, 2007). Recruitment of EPS15 and ITSN1 and 2 appears coincident with binding of FCHo2 and depends on direct interaction with the AP2 mu homology domain of FCHo2 (Henne et al, 2010).


SGIP1 (Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1) interacts with numerous endocytic proteins including AP-2, ITSN1, REPS1, EPS15, endophilin and amphiphsyin1 and is thought to play a role in clathrin-mediated endocytosis (Trevaskis et al, 2005; Dergai et al, 2010; Uezu et al, 2007). SGIP1 is related to the FCHo proteins and is co-immunoprecipitated in a tripartite complex containing ITSN1 and REPS1 (Dergai et al, 2010). The exact function of SGIP1 in clathrin-mediated endocytosis remains to be elucidated, however recent work suggests SGIP1 and FCHo proteins may contribute to allosteric changes in AP-2 that promote membrane binding and cargo recognition (Hollopeter et al, 2014).


The recruitment of this group of early CCP proteins is rapidly followed by the incorporation of many AP-2 and clathrin molecules, stimulated in part by the FCHo- and SGIP-dependent stabilization of the open, membrane binding conformation of AP-2 (Hollopeter et al, 2014). Alternately, a proportion of the nascent CCPs may undergo abortive initiation (Loerke et al, 2009; Aguet et al, 2013; Antonescu et al, 2011). This is prompted in part through the early recruitment of the 170 kDa isoform of synaptojanin 1 (SYNJ1-170, not shown in this reaction). SYNJ1 catalyzes the hydrolysis of PI(4,5)P2 to PI(4)P and destabilizes the interaction of many early CCP components with the plasma membrane (Perera et al, 2006).
R-HSA-8867754 (Reactome) BAR (BIN/amphiphysin/Rvs) domain proteins sense and contribute to membrane curvature. BAR domain proteins generally form long, coiled-coil homo- or hetero-dimers with a concave inner surface that interacts with membranes (reviewed in Gallop and McMahon, 2005; Daumke et al, 2014). F-BAR domain proteins such as FCHo 1 and 2 recognize shallow membrane curvature and are generally recruited early in the formation of clathrin-coated pit (Itoh et al, 2005; Kamioka et al, 2004; Henne et al, 2007; Shimada et al, 2007; Henne et al, 2010). FNBP proteins and N-BAR containing endocytic proteins such as SNX9 and 18, amphiphysin (AMPH) and endophilins recognize regions of membrane with greater curvature, interact with dynamin and likely play a later role in CCP formation with spatiotemporal coupling to vesicle scission (Kamioka et al, 2004; Itoh et al, 2005; Soulet et al, 2005; Shimada et al, 2007; Shin et al, 2008; Taylor et al, 2011; reveiwed in McMahon and Boucrot, 2011). These proteins are recruited to the complex through interactions with core components of the clathrin-coated pit, and in the case of SNX9, also through interaction with PI(3,4)P2, which is generated at late stages by clathrin-associated PIK3C2A (Lundmark and Carlson, 2003; Schmid et al, 2006; Dergai et al, 2010; Brett et al, 2002 : Posor et al, 2013; reviewed in Daumke et al, 2014). Early BAR domain containing proteins such as FCHo1 and 2 are not present in either late stage clathrin-coated pits or in free clathrin-coated vesicles. Although the precise timing of their dissociation is not known, in this pathway, they are shown leaving the clathrin-coated pit upon recruitment of the more highly curved N-BAR proteins (Taylor et al, 2011).
R-HSA-8867756 (Reactome) CLASP proteins are recruited to nascent clathrin-coated pits (CCPs) through interactions with AP-2 and clathrin. Although in this pathway cargo recruitment is depicted as occuring after the recruitment of bulk AP-2 and clathrin, a number of studies suggest that they are largely recruited concomitantly (Liu et al, 2010; reviewed in McMahon and Boucrot, 2011). Concurrent interactions with sorting signals in cargo cytoplasmic tails and with clathrin and/or AP-2 ensure that CLASPs and cargo are incorporated into the emerging CCP (Schmid et al, 2006; Edeling et al, 2006; reviewed in Traub, 2009; Traub and Bonifacino, 2013; Kirchausen et al, 2014). In addition, incorporation of CLASPs and cargo may play a role in regulating the timing and dynamics of endocytosis (Loerke et al, 2009; Mettlen et al, 2009; Soohoo et al, 2013; Mettlen et al, 2010; Puthenveedu et al, 2005).
R-HSA-8868066 (Reactome) Plasma membrane enrichment of PI(4,5)P2 is maintained in part through the action of PI 4 phosphatase 5 kinases (PIPKIs) such as PIP5K1C (Di Paolo and De Camilli, 2006). PIP5K1C interacts directly with AP-2 and the interaction activates the kinase, generating a positive feedback loop for the recruitment of AP-2 to the plasma membrane (Krauss et al, 2006; Bairstow et al, 2006; Thieman et al, 2009; reviewed in Daumke et al, 2014).
R-HSA-8868071 (Reactome) PIK3C2A is a member of the class II PI 3 kinases, and phosphorylates PI(4)P to PI(3,4)P2 at the plasma membrane. PIK3C2A interacts with clathrin through a clathrin-binding domain in its unique N-terminal tail and localizes to late-stage clathrin-coated pits (Domin et al, 2000; Gaidarov et al, 2001; Gaidarov et al, 2005). Binding to clathrin stimulates the kinase activity of PIK3C2A and promotes the production of PI(3,4)P2 at the plasma membrane (Gaidarov et al, 2001). PI(3,4)P2 formation by PIK3C2A contributes to maturation of clathrin-coated pits by promoting the recruitment of BAR-domain containing proteins such as SNX9, which stimulate membrane curvature required for vesicle formation and eventual fission (Posor et al, 2013; reveiwed in Daumke et al, 2014).
R-HSA-8868072 (Reactome) Clathrin-associated PIK3C2A catalyzes the conversion of PI(4)P to PI(3,4)P2, which contributes to the recruitment of BAR domain proteins such as SNX9 to the clathrin-coated pit (Domin et al, 2000; Gaidarov et al, 2001; Gaidarov et al, 2005; Posor et al, 2013; reviewed in Daumke et al, 2014).
R-HSA-8868230 (Reactome) Actin polymerization is not absolutely required for clathrin-mediated endocytosis, and disruption of actin does not interfere with the early stages of clathrin-coated pit formation. Actin is required to complete vesicle formation under conditions of high membrane tension, such as on the apical side of polarized epithelial cell, while actin is dispensable for this process in the absence of membrane tension (Boulant et al, 2011). In cases where actin is required, it appears to be recruited late to the emerging clathrin-coated pit, just prior to or coincident with the recruitment of dynamin and vesicle scission (Taylor et al, 2011; Taylor et al, 2012; reviewed in McMahon and Boucrot, 2011). Recruitment of actin depends on the ARP2/3 complex, and cortactin or the neural Wiscott-Aldrich syndrome proteins WASL. These proteins, in turn, are recruited through interactions with N-BAR domain containing proteins such as SNX9 (Yarar et al, 2007; Shin et al, 2007; Shin et al, 2008; Ferguson et al, 2009; reviewed in Lundmark and Carlsson, 2009; McMahon and Boucrot, 2011).
HIP1 and HIP1R are additional components of the late clathrin-coated pit that interact with clathrin and AP-2 and may contribute to actin nucleation (Waelter et al, 2001; Mishra et al, 2001;Metzler et al, 2001; Legendre-Guillemin et al, 2002; Wilbur et al, 2008; Taylor et al, 2011).
R-HSA-8868236 (Reactome) Dynamin is a large GTPase whose GTP hydrolysis activity is required for the scission of clathrin-coated vesicles from the plasma membrane (reviewed in Ferguson and De Camilli, 2012). Dynamin is recruited to the plasma membrane through protein-protein interactions with many components of the clathrin-coated pit including ITSNs, SNX9 and 18 and amphiphysin (Lundmark and Carlsson, 2003; Soulet et al, 2005; David et al, 1996; Owen et al, 1998; Shupliakov et al, 1997). Although dynamin is recruited at lower levels throughout formation of the clathrin-coated pit, the bulk of dynamin is recruited at late stages, after the incorporation of BAR domain-containing proteins and actin-polymerizing factors (Ferguson et al, 2009; Taylor et al, 2011; Taylor et al, 2012; Posor et al, 2013; Meineke et al, 2013; Aguet et al, 2013; reviewed in Daumke et al, 2014). Several BAR domain proteins have SH3 domains that bind the proline rich domain (PRD) of dynamin. These interactions regulate dynamin GTPsae activity and vesicle formation (Neuman and Schmid, 2013). To facilitate scission of a clathrin-coated pit from the plasma membrane, dynamin self assembles into helical oligomers, stimulating its GTPase activity and contributing to the membrane remodeling required to form the neck of the emerging vesicle (Sweitzer and Hinshaw 1998; Yoshida et al, 2004; Chappie et al, 2010; Faelber et al, 2011; Ford et al, 2011; reviewed in McMahon and Boucrot, 2011; Daumke et al, 2014).
R-HSA-8868648 (Reactome) Inositol-5-phosphatases like SYNJs and OCRL hydrolyze PI(4,5)P2 to PI(4)P. In the context of CME, this promotes the abortive turnover (disassembly) of some CCPs, contributes to the dynamin-mediated scission of the clathrin-coated vesicle neck, and promotes clathrin uncoating following scission (Guan et al, 2010; Cremona et al, 1999; Mani et al, 2007; Chang-Ileto et al, 2011; Antonescu et al, 2011; reviewed in McMahon and Boucrot, 2011; Daumke et al, 2014).
R-HSA-8868651 (Reactome) Synaptojanin (SYNJ) 1 and 2 are inositol-5-phosphatases that sequentially convert PI(4,5)P2 to PI(4)P and PI (Cremona et al 1999; reviewed in Billcliff and Lowe, 2014). Conversion of PI(4,5)P2 to PI(4)P and PI accompanies maturation of the clathrin-coated pit, and consistent with this, SYNJ proteins are recruited to the clathrin-coated pit through interactions with a number of endocytic proteins including ITSNs, EPS15, PACSIN proteins and endophilins, as well as with clathrin and AP-2 (Haffner et al, 1997; Cestra et al, 1999; Maire et al, 2004; Schuske et al, 2003; Verstreken et al, 2003; Modregger et al, 2000; Perera et al 2006; Milosevic et al, 2011; reviewed in Dittman and Ryan, 2009). SYJN1 exists in two isoforms, a longer 170 kDA isoform and a shorter 145 kDA isoform, with slightly different roles. The recruitment and activity of SYNJ1-145 appears to largely coincide with that of dynamin at later stages of vesicle formation, while the SYNJ1-170 isoform also plays earlier roles in stabilizing the growing clathrin-coated vesicle (Perera et al, 2006; Taylor et al, 2011; Antonescu et al, 2011). SYNJ-mediated hydrolysis of PI(4,5)P2 to PI(4)P is most efficient on highly curved, endophilin-coated tubules of the vesicle neck and contributes to dynamin-mediated membrane scission (Chang-Ileto et al, 2011; reviewed in Daumke et al, 2014; McMahon and Boucrot, 2011).

In addition to SYNJ1 and 2, other inositol-5-phosphatases are also recruited to the CCP at the time of scission. These include OCRL, which is recruited through interaction with clathrin as well as the RAB5 interactor APPL1 (Erdmann et al, 2007; Mao et al, 2009; Taylor et al, 2011; Nandez et al, 2014).
R-HSA-8868658 (Reactome) HSPA8 hydrolyzes ATP to promote dissociation of the clathrin coat from the vesicle (reviewed in Sousa and Lafer, 2015). Interaction of HSPA8 with the C-terminal tail of clathrin may sterically block re-stabilization of the clathrin coat, which is thought to undergo transient cycles of 'breathing', or loosening of the interactions between the triskelions (Barouch et al, 1997; Rapoport et al, 2008; Xing et al, 2010). Alternately, HSPA8 may destabilize the clathrin coat through intermolecular collisions with the coat (reveiwed in Sousa and Lafer, 2015). The HSPA8-clathrin interaction persists once clathrin has been removed from the vesicle. This is thought to preclude aberrant repolymerization of clathrin by sequestering free clathrin (Schlossman et al, 1984; reviewed in Sousa and Lafer, 2015).
R-HSA-8868659 (Reactome) After fission from the plasma membrane, auxilin proteins DNAJC6 and GAK are recruited to the vesicle through interaction with clathrin and phosphoinositides, in particular PI4P (Greener et al, 2000; Lee et al, 2006; Massol et al, 2006; Taylor et al, 2011; Scheele et al, 2001; Fotin et al, 2004a; Fotin et al, 2004b; Guan et al, 2010; reviewed in McMahon and Boucrot, 2011; Sousa and Lafer, 2015). Auxilin in turn recruits the ATPase HSPA8 (also known as HSC70) , which uses the energy from ATP hydrolysis to remove the clathrin-coat from the vesicle, priming it for fusion with a subsequent endosomal compartment (Schlossman et al, 1984; Ungewickell et al, 1995; Rappoport et al, 2008; Xing et al, 2010; Bocking et al, 2011; Rothnie et al, 2011; reviewed in McMahon and Boucrot, 2011; Sousa and Lafer, 2015).
R-HSA-8868660 (Reactome) HSPA8 (also known as HSC70) is recruited to the clathrin-coated vesicle through interaction with DNA J proteins GAK and DNAJC6 (Rapoport et al, 2008; Xing et al, 2010; reviewed in Sousa and Lafer, 2015). Recent studies examining the stoichiometry of uncoating predict between one and three HSPA8 molecules are required per clathrin triskelion for maximal uncoating in vitro (Bocking et al, 2011; Rothnie et al, 2011). After ATP hydrolysis, HSPA8 remains associated with the liberated clathrin, which prevents aberrant repolymerization and association of clathrin (Schlossman et al, 1984; reviewed in Sousa and Lafer, 2015).
R-HSA-8868661 (Reactome) Self-assembly of dynamin around the neck of the emerging clathrin-coated vesicle stimulates its GTPase activity. This in turn promotes a conformational change in dynamin organization that is required for membrane fission (Hinshaw and Schmid, 1995; Sweitzer and Hinshaw, 1998; Takei et al, 1999; Yoshida et al, 2004; Chappie et al, 2010; Chappie et al, 2011; Ford et al, 2011; Faelber et al, 2011; reviewed in Daumke et al, 2014).
R-HSA-8869438 (Reactome) After the removal of the clathrin coat, it is likely that many of the proteins that contributed to vesicle formation are lost, although the timing and mechanism of this step are poorly understood (reviewed in McMahon and Boucrot, 2011; Lemmon, 2001).
R-HSA-8871193 (Reactome) GAPVD1 binds the alpha adaptin ear domain of AP-2 mu2, activating its RAB5-directed GEF activity and displacing AAK1. AAK1 displacement results in a net dephosphorylation of the AP-2 mu2 subunit, destabilizing the interaction of AP-2 with the vesicle membrane (Sato et al, 2005; Smerdjieva et al, 2008). In addition, RAB5 contributes to PI(4,5)P2 turnover through recruitment of a PI3K or PI phosphatase, and this also destabilizes the interaction of AP-2 with the membrane (Smerdjieva et al, 2008; Christoforidis et al, 1999; Shin et al, 2005).
R-HSA-8871194 (Reactome) RAB5 is a small GTPase that is implicated in clathrin-mediated endocytosis (Chavrier et al, 1990; McLauchlan et al, 1998; Shin et al, 2002; Taylor et al, 2011; reviewed in Stenmark, 2009; Wandiger-Ness and Zerial, 2014). Recent studies have shown that RAB5 and its associated GEF GAPVD1 may contribute to AP-2 uncoating by displacing AAK1 and promoting the net dephosphorylation of the AP-2 mu2 subunit. This is predicted to destabilize interactions with the plasma membrane and promote uncoating (Sato et al, 2005; Hunker et al, 2006; Smerdjieva et al, 2008). RAB5 and GAPVD1 also increase PI(4,5)P2 turnover, likely through recruitment of a class I PI3K or a PI phosphatase (Christoforidis et al, 1999; Shin et al, 2005).
R-HSA-8871196 (Reactome) Assembly of an endocytic clathrin-coated pit (CCP) at the plasma membrane depends on the recruitment of the AP-2 adaptor protein complex and clathrin triskelions to the lipid bilayer (reviewed in McMahon and Boucrot, 2011; Robinson, 2015). Transient interactions between the plasma membrane-enriched lipid phosphatidlyinositol 4,5-bisphosphate (PI(4,5)P2) and AP-2 initiate coated pit formation (Beck et al, 1991; Honing et al, 2005; Loerke et al, 2009; Cocucci et al, 2012). A proportion of the transient complexes between AP-2, clathrin and the plasma membrane are rapidly stabilized by the recruitment of a number of proteins, including FCHo proteins, intersectins (ITSNs), EPS15 and SGIP1 among others (Henne et al, 2010; Stimpson et al, 2009; Reider et al, 2009; Cocucci et al, 2012; reviewed in McMahon and Boucrot, 2011). Many of these early players in CCP formation bind both to the plasma membrane and to the AP-2 complex and/or clathrin.

CCP formation is a highly heterogeneous and dynamic process and includes abortive initiation of nearly half of nascent CCPs (Loerke et al, 2009; Aguet et al, 2013). Heterogeneity is in part the result of the widely varied cargo proteins, which compete for a limited number of interaction hubs on AP-2 and clatrhin and influence the other protein components of the CCPs. Heterogeneity may also be partly stochastic, or be influenced by the presence of CCP 'hot spots' in the plasma membrane (Taylor et al, 2011; Antonescu et al, 2011; Gaidarov et al, 1999; Ehrlich et al, 2004; Saffarian et al, 2009; Nunez et al, 2011). It is important to note that although events in this pathway are depicted as occuring sequentially in a defined order, in reality the assembly of a clathrin-coated vesicle may be highly variable and the temporal boundaries are likely less clearly defined. Moreover, not every CCP will have all of the proteins indicated in this pathway.
REPS1ArrowR-HSA-8869438 (Reactome)
REPS1R-HSA-8862280 (Reactome)
SGIP1ArrowR-HSA-8869438 (Reactome)
SGIP1R-HSA-8862280 (Reactome)
SH3GLsArrowR-HSA-8869438 (Reactome)
SH3GLsR-HSA-8867754 (Reactome)
SNX9,18ArrowR-HSA-8869438 (Reactome)
SNX9,18R-HSA-8867754 (Reactome)
SYNJs,OCRLArrowR-HSA-8869438 (Reactome)
SYNJs,OCRLR-HSA-8868651 (Reactome)
TRIP10 dimerArrowR-HSA-8869438 (Reactome)
TRIP10 dimerR-HSA-8867754 (Reactome)
WASL,CTTNArrowR-HSA-8869438 (Reactome)
WASL,CTTNR-HSA-8868230 (Reactome)
clathrin triskelionR-HSA-8856808 (Reactome)
clathrin triskelionR-HSA-8871196 (Reactome)
clathrin:HSPA8:ADPArrowR-HSA-8868658 (Reactome)
f-actinArrowR-HSA-8869438 (Reactome)
f-actinR-HSA-8868230 (Reactome)
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