Signal regulatory protein family interactions (Homo sapiens)

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3, 5, 15-17115, 116, 7122, 4, 8, 9, 141, 2, 1810, 1311cytosolFYB CD47 p-Y428,Y452,Y469,Y495-SIRPA pSIRP-A:Grb2p-Y428,Y452,Y469,Y495-SIRPA PTK2BSP-A oligomer pSIRP-A:PYK2p-Y428,Y452,Y469,Y495-SIRPA p-Y428,Y452,Y469,Y495-SIRPA ATPGRB2-1SIRPA pSIRPalpha:CD47:SCAP2pSIRPalpha:CD47:SCAP2:FYBFYBSIRPA:SP-A/SP-DCD47 PTPN6 SIRP gamma:CD47FAK1 SIRPA:CD47SIRPA SP-A oligomer SHP2/SHP1:pSIRPalpha:CD47p-Y428,Y452,Y469,Y495-SIRPA ADPTYROBP SIRPG GRB2-1 PTPN6,PTPN11pSIRP alpha:CD47CD47 CD47 TYROBPPTPN11 SP-D oligomer SRC-1 SKAP2SIRP beta1:DAP12PTPN6 PTK2B PTPN11 CD47SIRPACD47 SIRPB1SP-D oligomer CD47 SIRPGp-Y428,Y452,Y469,Y495-SIRPA SKAP2 SKAP2 Pulmonory surfactantproteins A and DCD47 Src kinasesSrc/FADK1SIRPB1 CD47 6


Description

Signal regulatory protein (SIRP)alpha, also known as SHPS-1 or SIRPA or 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 SIRP alpha with CD47 is important for the regulation of migration and phagocytosis. SIRP alpha functions as a docking protein to recruit and activate SHP-1 or SHP-2 at the cell membrane in response to extracellular stimuli. SIRP alpha 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. SIRP alpha also binds the extracellular proteins, surfactant-A (SP-A) and surfactant-D (SP-D).
In addition to SIRP alpha there are two closely related proteins in the SIRP family namely SIRP beta and SIRP gamma. These three family proteins show high sequence similarity and similar extracellular structural topology, including three Ig domains, but their ligand binding topology might differ. SIRP beta is expressed on myeloid cells, including monocytes, granulocytes and DCs. A natural ligand for SIRP beta remains unknown; SIRP gamma can bind to CD47 but the binding affinity is lower than that of SIRP alpha. View original pathway at:Reactome.

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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:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CD47 ProteinQ08722 (Uniprot-TrEMBL)
CD47ProteinQ08722 (Uniprot-TrEMBL)
FAK1 ProteinQ05397 (Uniprot-TrEMBL)
FYB ProteinO15117 (Uniprot-TrEMBL)
FYBProteinO15117 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
PTK2B ProteinQ14289 (Uniprot-TrEMBL)
PTK2BProteinQ14289 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
PTPN6,PTPN11ComplexR-HSA-389744 (Reactome)
Pulmonory surfactant proteins A and DComplexR-HSA-391108 (Reactome)
SHP2/SHP1:pSIRP alpha:CD47ComplexR-HSA-391110 (Reactome)
SIRP beta1:DAP12ComplexR-HSA-210222 (Reactome)
SIRP gamma:CD47ComplexR-HSA-391166 (Reactome)
SIRPA ProteinP78324 (Uniprot-TrEMBL)
SIRPA:CD47ComplexR-HSA-391111 (Reactome)
SIRPA:SP-A/SP-DComplexR-HSA-391109 (Reactome)
SIRPAProteinP78324 (Uniprot-TrEMBL)
SIRPB1 ProteinO00241 (Uniprot-TrEMBL)
SIRPB1ProteinO00241 (Uniprot-TrEMBL)
SIRPG ProteinQ9P1W8 (Uniprot-TrEMBL)
SIRPGProteinQ9P1W8 (Uniprot-TrEMBL)
SKAP2 ProteinO75563 (Uniprot-TrEMBL)
SKAP2ProteinO75563 (Uniprot-TrEMBL)
SP-A oligomer R-HSA-391092 (Reactome)
SP-D oligomer R-HSA-391097 (Reactome)
SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
Src kinases Src/FADK1ComplexR-HSA-548936 (Reactome)
TYROBP ProteinO43914 (Uniprot-TrEMBL)
TYROBPProteinO43914 (Uniprot-TrEMBL)
p-Y428,Y452,Y469,Y495-SIRPA ProteinP78324 (Uniprot-TrEMBL)
pSIRP alpha:CD47:SCAP2:FYBComplexR-HSA-391116 (Reactome)
pSIRP alpha:CD47:SCAP2ComplexR-HSA-391118 (Reactome)
pSIRP alpha:CD47ComplexR-HSA-391115 (Reactome)
pSIRP-A:Grb2ComplexR-HSA-391112 (Reactome)
pSIRP-A:PYK2ComplexR-HSA-391113 (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)
Pulmonory surfactant proteins A and DR-HSA-391155 (Reactome)
R-HSA-210274 (Reactome) SIRP beta , also named CD172b, is expressed mainly on myeloid cells and has a very short cytoplasmic region of only six amino acids, lacking the signaling motifs for association with phosphatases that are found in the highly related SIRP alpha receptor. Instead, SIRP associates with a dimeric protein DAP12 to transmit activating signals via an ITAM in the cytoplasmic domain of DAP12. A positively charged amino acid in the transmembrane domain of DAP12 associate with a basic amino acid in SIRP beta's transmembrane region.
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. Recruitment of FYB to SIRP alpha requires SCAP in the SIRP alpha complex. The evidence for this interaction is from immunoprecipitation experiments performed in COS-7 lysates.
R-HSA-391152 (Reactome) Protein tyrosine kinase 2 beta (PYK2), a cytosolic tyrosine kinase related to FAK, has been shown to complex with SIRP alpha. The evidence for this interaction is from immunoprecipitation experiments performed in COS-7 lysates.
R-HSA-391153 (Reactome) Grb2 binds to phosphorylated tyrosine residues in SIRP alpha in vitro; this interaction has negative regulatory effects on cellular responses induced by growth factors, oncogenes or insulin.
R-HSA-391155 (Reactome) Pulmonary surfactant proteins A and D (SP-A and SP-D) are soluble multivalent ligands shown to bind SIRP alpha on resident alveolar cells and macrophages via their lectin domain (globular head). SP-A and SP-D bind to the same regions of SIRP alpha as CD47, as shown by their ability to block 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 is expressed by T cells and has been shown to engage with CD47, albeit with lower affinity than SIRP alpha. The engagement of SIRP gamma on the surface of T cells with cell-surface-expressed CD47 increased cell-cell adhesion.
SHP2/SHP1:pSIRP alpha:CD47ArrowR-HSA-391150 (Reactome)
SIRP beta1:DAP12ArrowR-HSA-210274 (Reactome)
SIRP gamma:CD47ArrowR-HSA-391168 (Reactome)
SIRPA:CD47ArrowR-HSA-391158 (Reactome)
SIRPA:CD47R-HSA-391156 (Reactome)
SIRPA:SP-A/SP-DArrowR-HSA-391155 (Reactome)
SIRPAR-HSA-391155 (Reactome)
SIRPAR-HSA-391158 (Reactome)
SIRPB1R-HSA-210274 (Reactome)
SIRPGR-HSA-391168 (Reactome)
SKAP2R-HSA-391157 (Reactome)
Src kinases Src/FADK1mim-catalysisR-HSA-391156 (Reactome)
TYROBPR-HSA-210274 (Reactome)
pSIRP alpha:CD47:SCAP2:FYBArrowR-HSA-391151 (Reactome)
pSIRP alpha:CD47:SCAP2ArrowR-HSA-391157 (Reactome)
pSIRP alpha:CD47:SCAP2R-HSA-391151 (Reactome)
pSIRP alpha:CD47ArrowR-HSA-391156 (Reactome)
pSIRP alpha:CD47R-HSA-391150 (Reactome)
pSIRP alpha:CD47R-HSA-391152 (Reactome)
pSIRP alpha:CD47R-HSA-391153 (Reactome)
pSIRP alpha:CD47R-HSA-391157 (Reactome)
pSIRP-A:Grb2ArrowR-HSA-391153 (Reactome)
pSIRP-A:PYK2ArrowR-HSA-391152 (Reactome)
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