Clathrin-mediated endocytosis (Homo sapiens)

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1, 4, 5, 16, 20...1, 5, 11, 53, 55...1, 3, 6, 7, 18...14, 20, 39, 66, 97...37, 92, 94, 139, 1501, 5, 20, 25, 37...1, 20, 24, 33, 34, 37...1, 20, 44, 52, 87...1, 7139, 66, 97, 1123, 8, 28, 92, 15850, 87, 100, 102, 1061, 17, 20, 22, 33...1, 29, 65, 88, 92...1, 5, 9, 20, 23...1, 4, 12, 15, 34...60, 64, 72, 75, 92...37, 92, 94, 139, 15026, 61, 87, 100, 102...27, 43, 67, 111, 1351, 2, 11, 13, 20...clathrin-coated endocytic vesiclecytosolPACSIN3 SYT11 ITSN2 SYT11 ITSN2 DAB2 AP2M1 EPS15 H2OSYT8 SNAP91 NECAP2 DNM1 NAd CLTB PI(3,4)P2TRIP10 LDLRAP1 UBC(609-684) EGF SYT8 STAM FNBP1 EPS15L1 STAM2 EPS15 AP2M1 PI4P SH3GL1 SYNJ2 EPN1 STON2 ARRB2 GAK APOB(28-4563) AP2A2(1-939) VAMP2 UBC(77-152) SNAP91 VAMP2 AP2S1 N-WASP GRB2-1 AVPR2 AP2M1 AP-2 YXXPhi cargo SNX18 EPN1 PI4P EPN1 SYT8 CHOL DNM3 ARRB1 SGIP1 p-T156 AP2M1 SH3GL3 CTTN ITSN2 SNAP91 STON1 EPN2 VAMP2 DNM:GDPADR EGF SNX18 UBC(1-76) AP2A2(1-939) SNAP91 STON1 APOB(28-4563) LRP2 VAMP8 AP2M1 CLTCL1 SNX18 CLTC CHRM2 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:GAPVD1APOB(28-4563) FNBP1 EGF UBC(609-684) FNBP1L N-WASP PI(4,5)P2 VAMP2 ARPC2 PACSIN1 f-actin N4GlycoAsn-PalmS WNT5A(36-380) VAMP7 CTTN DNM:GTPAP2A2(1-939) SNX9 AP2M1 pS-ADRB2 NECAP1 EPN2 VAMP2 ADPAP2M1 PI(4,5)P2 AAK1HGS p-6Y-EGFR N-WASP CLTC AP2A2(1-939) NECAP1 CLTA VAMP2 UBC(77-152) ARPC1A ATP DNM1 UBC(229-304) AP2B1 SYT1 AGFG1 AVPR2 AVPR2 SYNJ2 UBC(1-76) AVP(20-28) SGIP1 NECAP1 UBB(1-76) SYT1 SGIP1 GDP LRP2 TACR1 SH3GL1 HIP1 ATPp-Y371-CBL UBC(229-304) ARPC5 STON2 ATP NECAP1 SYT8 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:SYNJsSTAM2 UBB(1-76) AP-2 YXXPhi cargo GTP CLTCL1 GRB2-1 CLTC HIP1 dimerp-6Y-EGFR ARRB1 REPS2 APOB(28-4563) UBA52(1-76) SYT1 TRIP10 AAK1 AAK1 PACSIN1 VAMP3 APOB(28-4563) ADR CLTA pS-ADRB2 ITSN2 ACTR2 CLTC UBC(229-304) UBC(457-532) SH3GL3 SH3KBP1 p-T156 AP2M1 UBC(533-608) AP2S1 CHRM2 REPS2 VAMP2 UBC(229-304) AP2M1 VAMP3 SYT8 UBB(77-152) SYT8 ITSN2 CLTC VAMP8 AAK1 NECAP2 UBC(153-228) GTP NECAP1 SYT8 ARPC3 GGC-RAB5C ITSN2 VAMP7 HIP1 f-actin NECAP1 STON2 PI4P AMPH NECAP2 p-AVPR2 SYT2 TAGs UBC(609-684) LRP2 p-T156 AP2M1 VAMP7 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:SYNJsUBB(77-152) UBC(305-380) AMPH ACTR3 ITSN1 AP2M1 UBA52(1-76) SNAP91 ARRB2 EPS15 NECAP1 SGIP1 SNX9 ARRB2 EPS15L1 UBC(153-228) ARPC5 AP2S1 SH3GL1 PL AVPR2 FCHO1 UBC(381-456) REPS1 SYT1 LDLRAP1 p-Y850 EPS15 VAMP3 ARPC1A AP2A1 ATP N-WASP DNM3 RPS27A(1-76) APOB(28-4563) SYT8 ITSN2 UBC(609-684) EPS15L1 PL CLTC ITSN1 CHRM2 SNX9 PICALM ITSN2 UBC(153-228) ARRB1 UBC(77-152) N4GlycoAsn-PalmS WNT5A(36-380) CLTA DNM2 REPS1 LDLRAP1 AP-2 YXXPhi cargo AMPH:BIN1AP-2 dileucine-containing cargo ARPC5 AP2M1 NECAP2 cholesterol esters pS-ADRB2 p-6Y-EGFR AP2A2(1-939) HGS RPS27A(1-76) VAMP2 N-WASP ARPC4 SH3GL2 p-DVL2 STAM2 DAB2 EPS15 UBC(229-304) p-Y850 EPS15 CLTA AP2A1 LRP2 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 dimersUBB(153-228) EPS15L1 Cargo recognitionforclathrin-mediatedendocytosisUBC(305-380) ITSN2 GDP UBC(457-532) SNX9 AP2B1 EPS15 VAMP2 AGFG1 UBC(305-380) clathrin:HSPA8:ADPFNBP1L DNAJC6 ARFGAP1:ARF6:GTPp-6Y-EGFR AP2B1 REPS2 SYT8 UBC(1-76) UBB(77-152) p-Y371-CBL FNBP1L DNM2 ITSN2 SYNJ1 DAB2 UBC(457-532) UBA52(1-76) UBB(1-76) ARRB2 UBC(533-608) PICALM PACSIN1 ITSN1 NECAP2 GGC-RAB5C GDP CLTC CLTCL1 AP2A1 EPS15L1 LRP2 APOB(28-4563) SH3GL2 AP2B1 UBC(381-456) CTTN p-DVL2 ITSN1 SYT2 p-6Y-EGFR EPN2 AMPH SYT11 pS-ADRB2 GRB2-1 UBC(609-684) AP2A2(1-939) AP2B1 AP2A1 GRB2-1 UBC(305-380) HIP1R REPS2 NECAP2 UBC(381-456) UBC(77-152) BIN1 UBB(1-76) CLTA 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:SYNJsAAK1 CHRM2 AGFG1 SYT11 CTTN SH3GL1 ARPC5 AP2A2(1-939) ITSN1 PI(4,5)P2 SH3KBP1 UBC(77-152) AVP(20-28) GTP GAK SNX9,18HIP1R UBC(457-532) EPN1 SNX18 BIN1 DNM1 FNBP1L TAGs SH3GL3 p-6Y-EGFR TAGs GDP SNX9 LDLR p-DVL2 UBC(305-380) AGFG1 CLTA PACSIN2 AP-2 dileucine-containing cargo VAMP3 EPN1 CLTC AP2M1 AP2A1 SYT2 SYT9 UBA52(1-76) AP2S1 NAd GDP AP2A2(1-939) UBC(1-76) UBC(77-152) EPN1 SYNJ1 EGF DNM3 UBC(153-228) ARPC4 CLTCL1 NAd AGTR1 AP2S1 AP2B1 AP2B1 STAM PL NECAP2 SYT9 N4GlycoAsn-PalmS WNT5A(36-380) SYT1 p-Y850 EPS15 N4GlycoAsn-PalmS WNT5A(36-380) VAMP7 PI(4,5)P2 SYT11 FCHO2 AAK1 REPS2 p-AVPR2 ARFGAP1 ADR AP-2 YXXPhi cargo HGS STAM2 NECAP1 DNM2 SYT2 CHOL ARRB2 GRB2-1 OCRL NAd LRP2 STON2 UBB(1-76) CTTN SYT9 UBA52(1-76) OCRL AP2A1 AP2A1 SH3GL2 PL CLTC CHOL ARPC5 cholesterol esters AP2A2(1-939) PL GGC-RAB5A p-T156 AP2M1 AGTR1 SNAP91 LDLR FCHO2 UBB(77-152) STAM2 SH3GL2 SNAP91 AP2B1 EPN2 UBC(305-380) PIK3C2ACLTC SYNJ1 ARRB1 SYT8 ARPC3 HIP1R VAMP8 LDLRAP1 SNAP91 ADR UBC(1-76) NAd NAd AMPH UBA52(1-76) p-Y850 EPS15 SH3GL3 TRIP10 EGF ITSN1 VAMP7 PL VAMP8 UBC(533-608) AVPR2 ARRB1 pS-ADRB2 N4GlycoAsn-PalmS WNT5A(36-380) UBB(153-228) SGIP1 AP2M1 VAMP2 AMPH PI(4,5)P2 LDLRAP1 SNAP91 PL CLTA N4GlycoAsn-PalmS WNT5A(36-380) FZD4 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:ATPUBC(381-456) ADR STAM2 ITSN1 UBA52(1-76) H2OLDLRAP1 EPN2 CLTA ARPC1A EGF NECAP2 SNAP91 CLTB cholesterol esters ATP AP-2 ComplexGRB2-1 AVP(20-28) ARPC3 CLTB p-DVL2 AP-2 YXXPhi cargo SH3GL2 UBB(153-228) SYNJs,OCRLAGFG1 STON1 HIP1R AGFG1 EPN2 AP2B1 PL ATP DNM1 UBC(1-76) f-actin DNM1 CLTA STAM AP2A2(1-939) ITSN1 HGS CLTC TAGs STAM PICALM SYNJ2 AP-2 YXXPhi cargo CLTA CTTN GGC-RAB5B UBC(153-228) EPN2 SNAP91 ATP SNX9 VAMP8 APOB(28-4563) UBB(77-152) GRB2-1 TACR1 ARRB2 p-T156 AP2M1 p-Y850 EPS15 CLTB CLTCL1 SNX9 AP2A2(1-939) UBB(153-228) REPS1 AP2B1 TRIP10 AP2S1 DAB2 ARRB1 pS-ADRB2 DNM3 SH3GL2 EPS15L1 DAB2 SYT1 UBC(533-608) AP2A2(1-939) ITSN1 UBC(305-380) UBB(153-228) UBC(609-684) p-Y371-CBL DNAJC6 AGTR1 AAK1 UBC(305-380) AP2M1 STON2 FNBP1 CLTCL1 CLTCL1 UBC(229-304) FNBP1 VAMP3 SNAP91 AP-2 dileucine-containing cargo SYT11 ARPC1A LDLRAP1 SYNJ2 LDLR CLTCL1 p-T156 AP2M1 CLTC RPS27A(1-76) NAd EPN1 AGTR1 TRIP10 DNAJC6 ARPC3 SH3GL1 UBB(153-228) TAGs LDLR CLTC CHOL AP2S1 DNM3 AGFG1 LRP2 p-Y850 EPS15 SH3GL1 RPS27A(1-76) SYNJ1 SYT9 STAM2 CLTA NECAP1 UBC(153-228) DNM3 GAPVD1 UBC(609-684) AMPH SYT2 AP2S1 FZD4 SH3GL3 AP2A1 STAM FZD4 ACTR2 DNM1 SNX9 SH3KBP1 STON2 SYT1 PICALM AGTR1 AP-2 YXXPhi cargo DAB2 REPS1 EPS15 p-DVL2 N4GlycoAsn-PalmS WNT5A(36-380) RPS27A(1-76) STON1 UBC(381-456) VAMP2 AP2M1 SYT9 TRIP10 ARPC2 FNBP1 VAMP8 UBB(1-76) SNX18 ITSN1 PACSIN3 ITSN2 SYT1 p-6Y-EGFR LDLRAP1 CHRM2 SYT1 GGC-RAB5:GDP:GAPVD1SH3GL2 p-Y371-CBL SNX18 H2OHIP1R EPS15 EPS15UBC(381-456) UBC(381-456) SGIP1 VAMP8 SH3GL1 ARPC4 UBB(77-152) PICALM PACSIN2 UBB(1-76) UBC(457-532) CLTA LDLR SYT11 AP2B1 p-AVPR2 LDLR AP2B1 EPN1 FZD4 HIP1 PACSIN3 VAMP3 VAMP7 AP-2 dileucine-containing cargo STON1 STAM STON1 SYNJ1 EPN1 STON2 ITSN2 CLASP proteins:cargoITSN1 CLTA TAGs pS-ADRB2 ARPC1A GDP SYT2 f-actinPICALM STON1 SYT9 p-Y850 EPS15 CLTA UBB(1-76) UBB(1-76) AP2A2(1-939) PACSIN2 CLTC AMPH AP2B1 AP2A1 STON1 p-Y371-CBL GRB2-1 AP2S1 SYT8 CLTB FNBP1 VAMP8 CHRM2 AP2S1 ITSN2 NECAP2 UBB(77-152) SGIP1 GAPVD1 EPN2 FNBP1 EPN2 HGS SYT2 TACR1 HIP1 ITSN1 EPN2 ARRB1 ARPC2 PACSIN1 AVP(20-28) EPS15L1 SNX9 ITSN2 PACSIN dimersPIK3C2A cholesterol esters PACSIN3 SH3KBP1 HIP1 OCRL EPS15 VAMP3 PiUBC(457-532) PI4P PACSIN2 HIP1R CLTA ITSN2 CLTA AGTR1 AP2S1 CLTC CTTN AAK1 AP-2 dileucine-containing cargo NECAP2 AP-2 dileucine-containing cargo UBB(153-228) EPN2 SYT2 CHOL SH3GL3 ARPC2 ADR UBC(77-152) VAMP7 EPS15 LRP2 DNM3 SGIP1 SNX9 REPS1 SYNJ2 FNBP1L N4GlycoAsn-PalmS WNT5A(36-380) GDP UBC(77-152) EPS15 SYT2 BIN1 TRIP10 FNBP1L CLTA LDLR SH3KBP1 HGS SGIP1 STON1 UBC(77-152) CLTB SYT1 UBC(609-684) AP2B1 ACTR3 pS-ADRB2 STON2 AP2M1 UBC(609-684) APOB(28-4563) p-T156 AP2M1 SNAP91 UBC(305-380) AP2A1 AP2A1 LRP2 DNM2 CHOL TAGs GGC-RAB5A GAK,DNAJC6AP2S1 PACSIN2 SH3GL2 TAGs ARPC5 UBC(381-456) LDLR ARRB2 SH3GL2 ACTR2 p-6Y-EGFR REPS1 AVP(20-28) ITSN1 pS-ADRB2 REPS1 NECAP1 UBC(533-608) AP-2 dileucine-containing cargo AAK1 CLTCL1 PiDNM1 SNX9 SGIP1 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:auxilinEPS15 AP2A2(1-939) EPN1 UBA52(1-76) UBC(609-684) NECAP2 PACSIN3 AP-2 dileucine-containing cargo STAM EGF CHRM2 VAMP8 UBC(457-532) EPS15 UBB(153-228) ADP UBA52(1-76) RPS27A(1-76) SH3KBP1 CHRM2 SH3GL2 GRB2-1 CLTA FCHO2 VAMP8 VAMP3 SNX18 FZD4 STAM2 ARRB2 STON2 AVP(20-28) REPS2 VAMP8 SH3GL3 GAK DAB2 N4GlycoAsn-PalmS WNT5A(36-380) HIP1 ARPC4 p-DVL2 AP-2 dileucine-containing cargo EPS15L1 ITSN1 PACSIN2 UBC(77-152) VAMP8 ACTR3 AGFG1 SYT9 APOB(28-4563) VAMP2 PACSIN2 EPS15L1 p-Y371-CBL PI(4,5)P2DNM1 HGS SYT11 SYT2 CHOL VAMP2 GGC-RAB5C FZD4 ATP PI(4,5)P2:p-T156AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1SGIP1 GAPVD1 LDLR SYNJ1 SH3GL1 SH3GL2 PI(4,5)P2 GGC-RAB5A APOB(28-4563) SH3KBP1 AP-2 YXXPhi cargo f-actin AP-2 ComplexARPC3 ITSN1 EPN2 PL DAB2 PICALM p-T156 AP2M1 p-Y850 EPS15 ARRB1 AVP(20-28) SNX18 p-Y371-CBL HGS AVP(20-28) HIP1 AP2B1 NECAP2 CLTC TACR1 AP2A1 TACR1 AP2A2(1-939) EPN1 AAK1 FNBP1L SYNJ2 EPN1 TRIP10 N-WASP SH3GL2 VAMP7 AP2B1 EPS15 SH3GLsUBC(457-532) FNBP1L REPS2 RPS27A(1-76) SH3GL1 p-Y371-CBL TRIP10 APOB(28-4563) ARRB2 GAK ARRB2 SYNJ1 p-Y371-CBL CLTC CLTB SH3KBP1 PICALM AVP(20-28) NECAP1 ARF6 AP-2 YXXPhi cargo EGF DNM2 CLASP proteins:cargoHGS AP2A1 UBC(1-76) EGF p-T156 AP2M1 SH3KBP1 ATP clathrin triskelionpS-ADRB2 p-T156 AP2M1 AP2A2(1-939) NAd AP2A2(1-939) REPS2 UBA52(1-76) CLTC SH3KBP1 PACSIN3 SH3GL3 CLTCL1 GAPVD1 LRP2 ADR N-WASP SYT9 UBC(153-228) BIN1 PI4P PACSIN3 AP2B1 ARPC3 AVPR2 CLTCL1 UBC(1-76) p-Y371-CBL ADPSTON2 TACR1 UBC(457-532) DAB2 f-actin CLTCL1 UBC(457-532) ITSN2 CHOL ARRB1 SH3GL1 GGC-RAB5:GTP:GAPVD1AP-2 dileucine-containing cargo AGTR1 PICALM FZD4 p-Y850 EPS15 ITSN2 EPN1 EPN1 UBC(1-76) CLTB p-Y371-CBL REPS2 ITSN1 LRP2 HGS PL SH3KBP1 EPN1 AP2B1 ACTR3 ATP PACSIN1 CHRM2 PL CLTA REPS2 VAMP3 ATP cholesterol esters FNBP1 ITSN1 TAGs AAK1 AP2A2(1-939) AGTR1 PL N-WASP p-Y850 EPS15 APOB(28-4563) DNM2 GTP p-Y371-CBL BIN1 DAB2 UBC(77-152) AP2S1 UBB(77-152) REPS1 SYT2 UBC(229-304) pS-ADRB2 FCHO1 SNX18 AVP(20-28) ACTR2 ADR EPN1 SGIP1ARRB2 ACTR3 SH3KBP1 CLTCL1 CLTC STAM AP2B1 CLTA STON1 N4GlycoAsn-PalmS WNT5A(36-380) CLTC AAK1 CLTCL1 UBC(305-380) ARPC2 EPN1 UBB(153-228) ARRB2 ARPC2 RPS27A(1-76) ADR PACSIN2 SH3GL1 UBC(229-304) PI(4,5)P2 UBC(153-228) HIP1 cholesterol esters DNM2 TACR1 SYT2 CLTB VAMP7 AP2A1 VAMP3 CLTB PACSIN2 AP2A1 UBC(1-76) DNAJC6 p-DVL2 ADR DNM1 SH3KBP1 EPS15 p-AVPR2 AP-2 YXXPhi cargo ACTR3 UBC(229-304) AGFG1 LRP2 LDLR AP2S1 CLTC CHRM2 UBA52(1-76) GGC-RAB5B CLTA TRIP10 FZD4 UBC(229-304) AP2B1 p-6Y-EGFR REPS1 REPS1 HSPA8 SYT1 p-6Y-EGFR EPN2 LDLRAP1 CLTC ARPC2 EGF ACTR3 ARPC1A AVP(20-28) PI(4,5)P2 AP2A1 SYT11 CHOL CLTB AP2A1 VAMP8 STON1 REPS2 PACSIN3 STON1 p-T156 AP2M1 UBC(153-228) VAMP7 EPN1 REPS2 UBB(153-228) PACSIN3 SH3GL3 SYNJ1 STON2 N4GlycoAsn-PalmS WNT5A(36-380) CLTA FZD4 ARPC3 AP2A2(1-939) UBB(77-152) p-6Y-EGFR p-Y371-CBL HGS AP2M1 UBC(153-228) NAd SYT11 SYT9 OCRL STAM NECAP1 STAM AP2B1 DNM3 AMPH PI4PHGS p-Y371-CBL ATP CLTC SYT8 AMPH TACR1 AP-2 YXXPhi cargo SYT11 PI(4,5)P2:p-T156AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargoARPC1A UBA52(1-76) CHOL AP2M1 AP2M1 SH3GL1 REPS1BIN1 CLTB SNX18 UBC(609-684) ACTR2 SH3GL1 GRB2-1 pS-ADRB2 UBC(609-684) AP2A1 AP2A2(1-939) UBC(381-456) ARPC4 p-6Y-EGFR PACSIN1 FCHO1 AP2S1 UBC(533-608) OCRL PACSIN3 FZD4 AP2A1 EPN1 UBC(153-228) SYT1 AGTR1 CLTA SH3GL3 pS-ADRB2 SYNJ2 AP2A2(1-939) RPS27A(1-76) CLTCL1 ARPC1A EPN2 PI(4,5)P2:AP-2:clathrinf-actin cholesterol esters AP-2 YXXPhi cargo AGTR1 p-DVL2 AP2S1 cholesterol esters ARPC5 ARRB1 AP2A1 FNBP1L 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:auxilinUBC(457-532) AGFG1 p-Y371-CBL p-Y371-CBL STAM SH3GL3 REPS1 ARPC1A ARRB1 FZD4 UBB(1-76) AGFG1 ARPC2 ATPSTAM2 LDLRAP1 p-DVL2 VAMP3 p-DVL2 ACTR2 PACSIN2 STAM2 AP2A1 ARPC5 REPS1 ATP SGIP1 TACR1 AP-2 dileucine-containing cargo ARPC5 NECAP1 SYT11 CLTC ADPSTAM UBC(381-456) GRB2-1 TACR1 ARPC3 CLTC GRB2-1 p-6Y-EGFR ARRB1 UBC(77-152) cholesterol esters AGTR1 FNBP1 AVP(20-28) p-T156 AP2M1 GRB2-1 CLTA AP2S1 PACSIN1 p-Y371-CBL AGTR1 cholesterol esters SYT9 DAB2 AP2B1 DAB2 p-DVL2 cholesterol esters REPS2 VAMP7 STON1 LDLR p-Y850 EPS15 CLTC GGC-RAB5B UBC(153-228) SYT9 HIP1 SYT9 UBC(533-608) PACSIN3 STAM2 STAM PACSIN1 UBB(77-152) PICALM NAd EGF PI4PTACR1 EGF 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:auxilinf-actin STAM VAMP7 FCHO1,2 dimerAP2M1 AP2S1 p-6Y-EGFR UBC(153-228) RPS27A(1-76) BIN1 CHRM2 AGFG1 BIN1 DNAJC6 UBB(1-76) CLTA VAMP3 AP2B1 GRB2-1 UBC(457-532) HIP1 UBB(1-76) AP2M1 UBC(1-76) EPS15 GRB2-1 AP2B1 FCHO1 ARPC1A cholesterol esters ARPC4 AP2A1 TAGs RPS27A(1-76) N-WASP UBC(305-380) FNBP1L FCHO2 SGIP1 FZD4 PI(4,5)P2:p-T156AP-2:clathrin:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:F-BAR proteins:BAR domain proteinsSH3GL1 UBC(533-608) FCHO1 TACR1 ADR CHRM2 FZD4 AP2M1 TAGs HIP1R CTTN STAM UBC(1-76) EPN1 AP2B1 HSPA8:ATPp-6Y-EGFR DAB2 SYNJ2 UBB(153-228) UBC(533-608) cholesterol esters SYT1 EPS15L1 p-AVPR2 AP2M1 ARRB2 CTTN UBC(153-228) UBC(229-304) SGIP1 HIP1 AP2S1 p-AVPR2 DNM2 EPN2 PI4P PICALM ADR UBC(457-532) LDLRAP1 EGF N-WASP STON2 HIP1R VAMP3 NECAPsUBC(153-228) p-Y371-CBL OCRL UBC(305-380) EPS15 TAGs UBB(153-228) REPS1 GGC-RAB5B GTP FNBP1 NAd UBC(77-152) AP2S1 CHOL DAB2 UBC(381-456) LDLRAP1 UBC(381-456) PI(4,5)P2 FNBP1L PICALM VAMP8 AP-2 dileucine-containing cargo AP2A1 PACSIN1 pS-ADRB2 UBC(77-152) p-T156 AP2M1 PICALM cholesterol esters VAMP2 RPS27A(1-76) SYT9 EGF OCRL AP2A2(1-939) UBB(1-76) AP2B1 AP2A1 NECAP2 ARPC2 SYT1 ACTR2 SYT11 SGIP1 AP2B1 EPS15 LRP2 STAM2 ARPC3 NAd ARRB1 AP2S1 ADR CLTB UBC(533-608) PL TAGs AGTR1 GTP BIN1 HIP1R ARPC1A SNX9 FZD4 p-Y850 EPS15 AGFG1 AP-2 dileucine-containing cargo NAd UBB(77-152) PI(4,5)P2:AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1p-AVPR2 OCRL DNAJC6 ARPC2 UBC(533-608) UBC(533-608) ARRB2 EPN1 CLTB AP2A1 RPS27A(1-76) PICALM APOB(28-4563) UBB(77-152) ARPC4 CLTB CLTC SH3GL2 GAK REPS2 DNM1 AMPH DNM2 AMPH CHOL PACSIN1 GGC-RAB5A RPS27A(1-76) UBB(1-76) UBC(305-380) REPS1 LDLRAP1 HGS AP2S1 AP2A1 AP2S1 FCHO1 UBC(457-532) DAB2 AP2S1 AP2M1 SYT11 HIP1R dimerTACR1 AP2A1 p-Y371-CBL ARPC2 CLTA NECAP1 AGFG1 CHOL PI(4,5)P2:p-T156AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1:NECAPs:AAK1:CLASP proteins:cargo:PIK3C2ACLTCL1 SH3GL2 N-WASP UBC(609-684) UBB(153-228) SH3GL3 SH3KBP1 HIP1R ACTR2 UBC(609-684) VAMP3 UBC(381-456) STON1 CHOL LDLR AP2M1 SH3KBP1 ARPC4 SYNJ2 AP2A1 AP2A2(1-939) CLTA VAMP7 DNM3 ARP2/3 complexAP2A2(1-939) BIN1 f-actin CLTC AP2A2(1-939) STON2 PI(4,5)P2:AP-2:clathrin:FCHO1,2:ITSNs:EPS15:REPS1:SGIP1HIP1R NECAP1 CTTN SYT11 ARPC3 NAd PI4P PI(4,5)P2 p-Y850 EPS15 FNBP1L NAd HSPA8 N4GlycoAsn-PalmS WNT5A(36-380) SYT1 HGS PL AP2A1 f-actin DNM1 UBC(533-608) EPS15L1 CLTA ACTR3 CHOL NECAP2 p-DVL2 STON2 FCHO2 UBC(229-304) UBB(77-152) AVP(20-28) APOB(28-4563) CHRM2 GAK LRP2 UBB(77-152) UBB(1-76) p-DVL2 GTP ARRB1 TAGs DNM3 WASL,CTTNclathrin triskelionAVP(20-28) CLTB SGIP1 ARPC5 ARPC4 AAK1SNX18 AVP(20-28) AP2S1 AGTR1 AAK1 UBC(229-304) REPS1 UBC(1-76) BIN1 UBB(153-228) FNBP1 TRIP10 CLTCL1 NECAP2 ADR ARRB1 BIN1 PL DNM3 AP-2 dileucine-containing cargo UBC(457-532) cholesterol esters LDLR TRIP10 p-DVL2 pS-ADRB2 FCHO2 TACR1 LDLRAP1 p-Y371-CBL CTTN VAMP7 PiGGC-RAB5C UBC(609-684) AGFG1 GDP EPS15L1 UBC(229-304) p-Y850 EPS15 LRP2 ACTR3 CLTC SYT2 EPS15 PICALM EGF AP2M1 N4GlycoAsn-PalmS WNT5A(36-380) ATPSTAM2 TAGs DNM2 PACSIN3 VAMP3 UBB(153-228) UBC(305-380) PACSIN2 STON1 ACTR2 UBA52(1-76) AP2M1 AP-2 YXXPhi cargo AAK1 UBA52(1-76) NECAP1 p-Y371-CBL VAMP7 UBC(533-608) UBC(229-304) AAK1 SH3GL1 AMPH SNAP91 TRIP10 dimerARPC4 OCRL ARPC3 CHRM2 SH3GL2 AP2A2(1-939) p-Y371-CBL UBA52(1-76) HSPA8 FNBP1 SYT8 UBC(381-456) CLTB AP2A2(1-939) UBC(1-76) f-actin AP2B1 AP-2 YXXPhi cargo STON2 ACTR2 SNX18 SH3GL3 EPN1 N4GlycoAsn-PalmS WNT5A(36-380) EPS15L1 SYT2 AP2S1 ARRB2 AP2M1 REPS2 FZD4 AGTR1 p-AVPR2 SH3GL1 SH3GL3 AP2S1 NECAP2 SH3GL3 SYNJ1 STAM2 ARPC4 PI4PEPS15L1 AP2S1 FNBP1 dimerSYT8 UBC(305-380) AP2S1 UBC(77-152) SH3GL2 ACTR3 UBC(381-456) CLTA p-Y850 EPS15 SYT8 SH3GL3 PACSIN1 LDLR SNAP91 p-Y371-CBL ARPC5 ACTR3 VAMP2 UBB(77-152) N4GlycoAsn-PalmS WNT5A(36-380) AP2A2(1-939) EPS15L1 SYT9 FNBP1L dimerAP-2 dileucine-containing cargo PACSIN1 CHRM2 ITSNsLDLRAP1 ADR AP2B1 DNM2 ACTR2 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:GTPp-DVL2 RPS27A(1-76) STAM2 SYT9 UBC(1-76) AP2M1 SYT2 EPN1 UBC(533-608) HGS PACSIN2 PIP5K1CAP2A2(1-939) AP-2 YXXPhi cargo VAMP8 REPS1 LDLR TACR1 AVPR2 AP2M1 42, 74, 81, 85, 9019, 31, 35, 136, 144...42, 74, 81, 85, 9019, 31, 35, 136, 144...19, 31, 35, 136, 144...19, 31, 35, 136, 144...19, 31, 35, 136, 144...19, 31, 35, 136, 144...42, 74, 81, 85, 9042, 74, 81, 85, 9042, 74, 81, 85, 9042, 74, 81, 85, 9053, 12942, 74, 81, 85, 9019, 31, 35, 136, 144...19, 31, 35, 136, 144...42, 74, 81, 85, 9019, 31, 35, 136, 144...19, 31, 35, 136, 144...42, 74, 81, 85, 9019, 31, 35, 136, 144...42, 74, 81, 85, 9019, 31, 35, 136, 144...42, 74, 81, 85, 9010, 47, 53, 76, 78...19, 31, 35, 136, 144...42, 74, 81, 85, 9042, 74, 81, 85, 9019, 31, 35, 136, 144...19, 31, 35, 136, 144...42, 74, 81, 85, 9042, 74, 81, 85, 90


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: 63
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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