Signal regulatory protein family interactions (Homo sapiens)

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4, 10, 12, 15, 1632, 5, 13, 14, 178, 181, 11, 1396, 799, 16cytosolp-Y428,Y452,Y469,Y495-SIRPA CD47 SIRPB1:TYROBPSFTPA oligomer,SFTPD oligomerCD47 CD47SIRPA:SFTPAoligomer, SFTPDoligomerPTPN6 CD47 TYROBP CD47 PTPN6,PTPN11SRC-1, PTK2TYROBPSIRPA SFTPA oligomer SIRPA:CD47PTPN6 SFTPD oligomer p-Y428,Y452,Y469,Y495-SIRPA p-Y428,Y452,Y469,Y495-SIRPA:CD47:PTK2BSIRPA SIRP gamma:CD47SKAP2 FYB SIRPAGRB2-1SKAP2CD47 PTK2B CD47 p-Y428,Y452,Y469,Y495-SIRPA:CD47:SKAP2p-Y428,Y452,Y469,Y495-SIRPA:CD47:GRB2-1PTK2BADPp-Y428,Y452,Y469,Y495-SIRPA SKAP2 PTPN11 CD47 p-Y428,Y452,Y469,Y495-SIRPA:CD47CD47 p-Y428,Y452,Y469,Y495-SIRPA SIRPB1 p-Y428,Y452,Y469,Y495-SIRPA:PTPN6,PTPN11SFTPA oligomer ATPp-Y428,Y452,Y469,Y495-SIRPA p-Y428,Y452,Y469,Y495-SIRPA PTK2 SRC-1 FYBSIRPB1SIRPG p-Y428,Y452,Y469,Y495-SIRPA:CD47:SKAP2:FYBSFTPD oligomer SIRPGPTPN11 GRB2-1 6


Description

Signal regulatory protein alpha (SIRPA, SHPS1, CD172a) is a transmembrane protein expressed mostly on myeloid cells. CD47, a widely expressed transmembrane protein, is a ligand for SIRP alpha, with the two proteins constituting a cell-cell communication system. The interaction of SIRPA with CD47 is important for the regulation of migration and phagocytosis. SIRPA functions as a docking protein to recruit and activate PTPN6 (SHP-1) or PTPN11 (SHP-2) at the cell membrane in response to extracellular stimuli. SIRPA also binds other intracellular proteins including the adaptor molecules Src kinase-associated protein (SKAP2 SKAP55hom/R), Fyn-binding protein/SLP-76-associated phosphoprotein (FYB/SLAP-130) and the tyrosine kinase PYK2. SIRPA also binds the extracellular proteins, surfactant-A (SP-A) and surfactant-D (SP-D).
The SIRP family members SIRPB and SIRPG show high sequence similarity and similar extracellular structural topology, including three Ig domains, but their ligand binding topology might differ. SIRPB is expressed on myeloid cells, including monocytes, granulocytes and DCs. It has no known natural ligand. SIRPG can bind CD47 but with lower affinity than SIRPA. View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 391160
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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Bibliography

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  1. Brooke G, Holbrook JD, Brown MH, Barclay AN.; ''Human lymphocytes interact directly with CD47 through a novel member of the signal regulatory protein (SIRP) family.''; PubMed Europe PMC Scholia
  2. Hatherley D, Graham SC, Harlos K, Stuart DI, Barclay AN.; ''Structure of signal-regulatory protein alpha: a link to antigen receptor evolution.''; PubMed Europe PMC Scholia
  3. Kharitonenkov A, Chen Z, Sures I, Wang H, Schilling J, Ullrich A.; ''A family of proteins that inhibit signalling through tyrosine kinase receptors.''; PubMed Europe PMC Scholia
  4. Matozaki T, Murata Y, Okazawa H, Ohnishi H.; ''Functions and molecular mechanisms of the CD47-SIRPalpha signalling pathway.''; PubMed Europe PMC Scholia
  5. Hatherley D, Graham SC, Turner J, Harlos K, Stuart DI, Barclay AN.; ''Paired receptor specificity explained by structures of signal regulatory proteins alone and complexed with CD47.''; PubMed Europe PMC Scholia
  6. Kishore U, Greenhough TJ, Waters P, Shrive AK, Ghai R, Kamran MF, Bernal AL, Reid KB, Madan T, Chakraborty T.; ''Surfactant proteins SP-A and SP-D: structure, function and receptors.''; PubMed Europe PMC Scholia
  7. Gardai SJ, Xiao YQ, Dickinson M, Nick JA, Voelker DR, Greene KE, Henson PM.; ''By binding SIRPalpha or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation.''; PubMed Europe PMC Scholia
  8. Tomasello E, Cant C, Bühring HJ, Vély F, André P, Seiffert M, Ullrich A, Vivier E.; ''Association of signal-regulatory proteins beta with KARAP/DAP-12.''; PubMed Europe PMC Scholia
  9. Timms JF, Swanson KD, Marie-Cardine A, Raab M, Rudd CE, Schraven B, Neel BG.; ''SHPS-1 is a scaffold for assembling distinct adhesion-regulated multi-protein complexes in macrophages.''; PubMed Europe PMC Scholia
  10. Liu Y, Bühring HJ, Zen K, Burst SL, Schnell FJ, Williams IR, Parkos CA.; ''Signal regulatory protein (SIRPalpha), a cellular ligand for CD47, regulates neutrophil transmigration.''; PubMed Europe PMC Scholia
  11. Piccio L, Vermi W, Boles KS, Fuchs A, Strader CA, Facchetti F, Cella M, Colonna M.; ''Adhesion of human T cells to antigen-presenting cells through SIRPbeta2-CD47 interaction costimulates T-cell proliferation.''; PubMed Europe PMC Scholia
  12. Barclay AN, Brown MH.; ''The SIRP family of receptors and immune regulation.''; PubMed Europe PMC Scholia
  13. Seiffert M, Cant C, Chen Z, Rappold I, Brugger W, Kanz L, Brown EJ, Ullrich A, Bühring HJ.; ''Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving its counterreceptor CD47.''; PubMed Europe PMC Scholia
  14. Hatherley D, Harlos K, Dunlop DC, Stuart DI, Barclay AN.; ''The structure of the macrophage signal regulatory protein alpha (SIRPalpha) inhibitory receptor reveals a binding face reminiscent of that used by T cell receptors.''; PubMed Europe PMC Scholia
  15. van den Berg TK, van Beek EM, Bühring HJ, Colonna M, Hamaguchi M, Howard CJ, Kasuga M, Liu Y, Matozaki T, Neel BG, Parkos CA, Sano S, Vignery A, Vivier E, Wright M, Zawatzky R, Barclay AN.; ''A nomenclature for signal regulatory protein family members.''; PubMed Europe PMC Scholia
  16. Oshima K, Ruhul Amin AR, Suzuki A, Hamaguchi M, Matsuda S.; ''SHPS-1, a multifunctional transmembrane glycoprotein.''; PubMed Europe PMC Scholia
  17. Liu Y, Tong Q, Zhou Y, Lee HW, Yang JJ, Bühring HJ, Chen YT, Ha B, Chen CX, Yang Y, Zen K.; ''Functional elements on SIRPalpha IgV domain mediate cell surface binding to CD47.''; PubMed Europe PMC Scholia
  18. Dietrich J, Cella M, Seiffert M, Bühring HJ, Colonna M.; ''Cutting edge: signal-regulatory protein beta 1 is a DAP12-associated activating receptor expressed in myeloid cells.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114854view16:35, 25 January 2021ReactomeTeamReactome version 75
113300view11:37, 2 November 2020ReactomeTeamReactome version 74
112512view15:47, 9 October 2020ReactomeTeamReactome version 73
101424view11:30, 1 November 2018ReactomeTeamreactome version 66
100962view21:07, 31 October 2018ReactomeTeamreactome version 65
100499view19:41, 31 October 2018ReactomeTeamreactome version 64
100045view16:25, 31 October 2018ReactomeTeamreactome version 63
99597view14:59, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99215view12:43, 31 October 2018ReactomeTeamreactome version 62
94492view08:56, 14 September 2017MkutmonReactome release 61
86677view09:24, 11 July 2016ReactomeTeamreactome version 56
83190view10:19, 18 November 2015ReactomeTeamVersion54
81563view13:06, 21 August 2015ReactomeTeamVersion53
77029view08:32, 17 July 2014ReactomeTeamFixed remaining interactions
76734view12:09, 16 July 2014ReactomeTeamFixed remaining interactions
76060view10:12, 11 June 2014ReactomeTeamRe-fixing comment source
75770view11:27, 10 June 2014ReactomeTeamReactome 48 Update
75120view14:07, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74767view08:51, 30 April 2014ReactomeTeamReactome46
45225view17:35, 7 October 2011KhanspersOntology Term : 'myeloid cell' added !
42125view21:58, 4 March 2011MaintBotAutomatic update
39935view05:57, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
CD47 ProteinQ08722 (Uniprot-TrEMBL)
CD47ProteinQ08722 (Uniprot-TrEMBL)
FYB ProteinO15117 (Uniprot-TrEMBL)
FYBProteinO15117 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
PTK2 ProteinQ05397 (Uniprot-TrEMBL)
PTK2B ProteinQ14289 (Uniprot-TrEMBL)
PTK2BProteinQ14289 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
PTPN6,PTPN11ComplexR-HSA-389744 (Reactome)
SFTPA oligomer R-HSA-391092 (Reactome)
SFTPA oligomer, SFTPD oligomerComplexR-HSA-391108 (Reactome)
SFTPD oligomer R-HSA-391097 (Reactome)
SIRP gamma:CD47ComplexR-HSA-391166 (Reactome)
SIRPA ProteinP78324 (Uniprot-TrEMBL)
SIRPA:CD47ComplexR-HSA-391111 (Reactome)
SIRPA:SFTPA

oligomer, SFTPD

oligomer		ComplexR-HSA-391109 (Reactome)
SIRPAProteinP78324 (Uniprot-TrEMBL)
SIRPB1 ProteinO00241 (Uniprot-TrEMBL)
SIRPB1:TYROBPComplexR-HSA-210222 (Reactome)
SIRPB1ProteinO00241 (Uniprot-TrEMBL)
SIRPG ProteinQ9P1W8 (Uniprot-TrEMBL)
SIRPGProteinQ9P1W8 (Uniprot-TrEMBL)
SKAP2 ProteinO75563 (Uniprot-TrEMBL)
SKAP2ProteinO75563 (Uniprot-TrEMBL)
SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
SRC-1, PTK2ComplexR-HSA-548936 (Reactome)
TYROBP ProteinO43914 (Uniprot-TrEMBL)
TYROBPProteinO43914 (Uniprot-TrEMBL)
p-Y428,Y452,Y469,Y495-SIRPA ProteinP78324 (Uniprot-TrEMBL)
p-Y428,Y452,Y469,Y495-SIRPA:CD47:GRB2-1ComplexR-HSA-391112 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47:PTK2BComplexR-HSA-391113 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47:SKAP2:FYBComplexR-HSA-391116 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47:SKAP2ComplexR-HSA-391118 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47ComplexR-HSA-391115 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:PTPN6,PTPN11ComplexR-HSA-391110 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-391156 (Reactome)
ATPR-HSA-391156 (Reactome)
CD47R-HSA-391158 (Reactome)
CD47R-HSA-391168 (Reactome)
FYBR-HSA-391151 (Reactome)
GRB2-1R-HSA-391153 (Reactome)
PTK2BR-HSA-391152 (Reactome)
PTPN6,PTPN11R-HSA-391150 (Reactome)
R-HSA-210274 (Reactome) SIRP beta (SIRPB, CD172b) is expressed mainly on myeloid cells and has a very short cytoplasmic region of only six amino acids, lacking the signaling motifs required for association with phosphatases that are found in SIRPA. Instead, SIRPB associates with a dimeric protein TYROBP (DAP12) to transmit activating signals via its ITAM motif. A positively charged amino acid in the transmembrane domain of TYROBP associates with a basic amino acid in the transmembrane region of SIRPB.
R-HSA-391150 (Reactome) SIRP alpha functions as a docking protein. The tyrosine-phosphorylated residues of SIRP alpha trigger the binding and activation of tyrosine phosphatases SHP-1 and SHP-2. All four phosphotyrosines of SIRP alpha may serve as substrates for SHP-1 and SHP-2. SIRP alpha binds mostly to SHP-1 in hematopoietic cells and with SHP-2 in non-hematopoietic cells. These phosphatases mediate the specific functions of SIRP alpha.
R-HSA-391151 (Reactome) The Fyn binding protein FYB (SLAP130, ADAP) has been found to associate with SIRP alpha (SIRPA). Recruitment of FYB to SIRPA requires SKAP2.
R-HSA-391152 (Reactome) Protein-tyrosine kinase 2-beta (PTK2B, PYK2, FADK2), a cytosolic tyrosine kinase related to FAK, has been shown to complex with SIRP alpha.
R-HSA-391153 (Reactome) GRB2 binds to phosphorylated tyrosine residues in SIRP alpha (SIRPA) in vitro; this interaction has negative regulatory effects on cellular responses induced by growth factors, oncogenes or insulin.
R-HSA-391155 (Reactome) Pulmonary surfactant-associated proteins A1, A2 and D (SFTPA1, SFTPA2 and SFTPD) are soluble multivalent ligands shown to bind SIRP alpha (SIRPA) on resident alveolar cells and macrophages via their lectin domain (globular head). SFTPA and SFTPD bind to the same region of SIRPA as CD47, blocking subsequent binding of CD47.
R-HSA-391156 (Reactome) Various growth factors and events such as integrin-mediated cell adhesion to extracellular matrix (ECM) proteins induce the tyrosine phosphorylation of SIRP alpha. The cytoplasmic tail of SIRP alpha has two ITIMs with four tyrosine residues that are potential sites for phosphorylation. Phosphorylation is not dependent on CD47 engagement but the presence of CD47 may enhance the effect. Src family kinases may be involved in the phosphorylation.
R-HSA-391157 (Reactome) SRC-family-associated phosphoprotein 2 (SCAP2) has been shown to bind to SIRP alpha. Evidence from immunoprecipitation experiments performed in COS-7 lysates suggests that the SH3 domain of SCAP2 is involved in the interaction.
R-HSA-391158 (Reactome) CD47 is an extracellular ligand for SIRP alpha. SIRP alpha directly binds to the loops of the Ig variable like domain of CD47 in an end-to-end fashion. The SIRP alpha/CD47 interaction is unusual in that it can lead to bidirectional signaling through SIRP alpha and CD47. The major function of this interaction is prevention of phagocytosis of RBC and platelets by macrophages.
R-HSA-391168 (Reactome) SIRP gamma (SIRPG) is expressed by T cells and has been shown to engage with CD47, albeit with lower affinity than SIRP alpha. The engagement of SIRPG on the surface of T cells increased cell-cell adhesion.
SFTPA oligomer, SFTPD oligomerR-HSA-391155 (Reactome)
SIRP gamma:CD47ArrowR-HSA-391168 (Reactome)
SIRPA:CD47ArrowR-HSA-391158 (Reactome)
SIRPA:CD47R-HSA-391156 (Reactome)
SIRPA:SFTPA

oligomer, SFTPD

oligomer		ArrowR-HSA-391155 (Reactome)
SIRPAR-HSA-391155 (Reactome)
SIRPAR-HSA-391158 (Reactome)
SIRPB1:TYROBPArrowR-HSA-210274 (Reactome)
SIRPB1R-HSA-210274 (Reactome)
SIRPGR-HSA-391168 (Reactome)
SKAP2R-HSA-391157 (Reactome)
SRC-1, PTK2mim-catalysisR-HSA-391156 (Reactome)
TYROBPR-HSA-210274 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47:GRB2-1ArrowR-HSA-391153 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47:PTK2BArrowR-HSA-391152 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47:SKAP2:FYBArrowR-HSA-391151 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47:SKAP2ArrowR-HSA-391157 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47:SKAP2R-HSA-391151 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47ArrowR-HSA-391156 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47R-HSA-391150 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47R-HSA-391152 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47R-HSA-391153 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:CD47R-HSA-391157 (Reactome)
p-Y428,Y452,Y469,Y495-SIRPA:PTPN6,PTPN11ArrowR-HSA-391150 (Reactome)
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