Signal-regulatory protein alpha
Signal regulatory protein α (SIRPα) is a regulatory membrane glycoprotein from SIRP family expressed mainly by myeloid cells and also by stem cells[citation needed ] or neurons.
SIRPα acts as inhibitory receptor and interacts with a broadly expressed transmembrane protein CD47 also called the "don't eat me" signal. This interaction negatively controls effector function of innate immune cells such as host cell phagocytosis. SIRPα diffuses laterally on the macrophage membrane and accumulates at a phagocytic synapse to bind CD47 and signal 'self', which inhibits the cytoskeleton-intensive process of phagocytosis by the macrophage.[5] This is analogous to the self signals provided by MHC class I molecules to NK cells via Ig-like or Ly49 receptors.[6] [7] NB. Protein shown to the right is CD47 not SIRP α.
Structure
[edit ]The cytoplasmic region of SIRPα is highly conserved between rats, mice and humans. Cytoplasmic region contains a number of tyrosine residues, which likely act as ITIMs. Upon CD47 ligation, SIRPα is phosphorylated and recruits phosphatases like SHP1 and SHP2.[8] The extracellular region contains three Immunoglobulin superfamily domains – single V-set and two C1-set IgSF domains. SIRP β and γ have the similar extracellular structure but different cytoplasmic regions giving contrasting types of signals. SIRP α polymorphisms are found in ligand-binding IgSF V-set domain but it does not affect ligand binding. One idea is that the polymorphism is important to protect the receptor of pathogens binding.[6] [9]
Ligands
[edit ]SIRPα recognizes CD47, an anti-phagocytic signal that distinguishes live cells from dying cells. CD47 has a single Ig-like extracellular domain and five membrane spanning regions. The interaction between SIRPα and CD47 can be modified by endocytosis or cleavage of the receptor, or interaction with surfactant proteins. Surfactant protein A and D are soluble ligands, highly expressed in the lungs, that bind to the same region of SIRPα as CD47 and can therefore competitively block binding.[9] [10]
Signalling
[edit ]The extracellular domain of SIRP α binds to CD47 and transmits intracellular signals through its cytoplasmic domain. CD47-binding is mediated through the NH2-terminal V-like domain of SIRP α. The cytoplasmic region contains four ITIMs that become phosphorylated after binding of ligand. The phosphorylation mediates activation of tyrosine kinase SHP2. SIRP α has been shown to bind also phosphatase SHP1, adaptor protein SCAP2 and FYN-binding protein. Recruitment of SHP phosphatases to the membrane leads to the inhibition of myosin accumulation at the cell surface and results in the inhibition of phagocytosis.[9] [10]
Cancer
[edit ]Cancer cells highly expressed CD47 that activate SIRP α and inhibit macrophage-mediated destruction. In one study, they engineered high-affinity variants of SIRP α that antagonized CD47 on cancer cells and caused increase phagocytosis of cancer cells.[11] Another study (in mice) found anti-SIRPα antibodies helped macrophages to reduce cancer growth and metastasis, alone and in synergy with other cancer treatments.[12] [13]
References
[edit ]- ^ a b c GRCh38: Ensembl release 89: ENSG00000198053 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000037902 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Tsai RK, Discher DE (March 2008). "Inhibition of "self" engulfment through deactivation of myosin-II at the phagocytic synapse between human cells". The Journal of Cell Biology. 180 (5): 989–1003. doi:10.1083/jcb.200708043. PMC 2265407 . PMID 18332220.
- ^ a b Barclay AN (February 2009). "Signal regulatory protein alpha (SIRPalpha)/CD47 interaction and function". Current Opinion in Immunology. 21 (1): 47–52. doi:10.1016/j.coi.200901008. PMC 3128989 . PMID 19223164.
- ^ Stefanidakis M, Newton G, Lee WY, Parkos CA, Luscinskas FW (August 2008). "Endothelial CD47 interaction with SIRPgamma is required for human T-cell transendothelial migration under shear flow conditions in vitro". Blood. 112 (4): 1280–1289. doi:10.1182/blood-2008年01月13日4429. PMC 2515120 . PMID 18524990.
- ^ Okazawa H, Motegi S, Ohyama N, Ohnishi H, Tomizawa T, Kaneko Y, et al. (February 2005). "Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system". Journal of Immunology. 174 (4): 2004–2011. doi:10.4049/jimmunol.174.4.2004 . PMID 15699129.
- ^ a b c Barclay AN, Brown MH (June 2006). "The SIRP family of receptors and immune regulation". Nature Reviews. Immunology. 6 (6): 457–464. doi:10.1038/nri1859. PMID 16691243. S2CID 7915923.
- ^ a b van Beek EM, Cochrane F, Barclay AN, van den Berg TK (December 2005). "Signal regulatory proteins in the immune system". Journal of Immunology. 175 (12): 7781–7787. doi:10.4049/jimmunol.175.12.7781 . PMID 16339510.
- ^ Weiskopf K, Ring AM, Ho CC, Volkmer JP, Levin AM, Volkmer AK, et al. (July 2013). "Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies". Science. 341 (6141): 88–91. Bibcode:2013Sci...341...88W. doi:10.1126/science.1238856. PMC 3810306 . PMID 23722425.
- ^ Potential new cancer treatment activates cancer-engulfing cells. Feb 2017
- ^ Yanagita T, Murata Y, Tanaka D, Motegi SI, Arai E, Daniwijaya EW, et al. (January 2017). "Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy". JCI Insight. 2 (1): e89140. doi:10.1172/jci.insight.89140. PMC 5214103 . PMID 28097229.
Further reading
[edit ]- Oldenborg PA (2013). "CD47: A Cell Surface Glycoprotein Which Regulates Multiple Functions of Hematopoietic Cells in Health and Disease". ISRN Hematology. 2013: 614619. doi:10.1155/2013/614619 . PMC 3564380 . PMID 23401787.
- Yamauchi T, Takenaka K, Urata S, Shima T, Kikushige Y, Tokuyama T, et al. (February 2013). "Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment". Blood. 121 (8): 1316–1325. doi:10.1182/blood-2012-06-440354 . PMID 23293079.
- Oldenborg PA (July 2004). "Role of CD47 in erythroid cells and in autoimmunity". Leukemia & Lymphoma. 45 (7): 1319–1327. doi:10.1080/1042819042000201989. PMID 15359629. S2CID 12642148.
- Margolis RL, Breschel TS, Li SH, Kidwai AS, Antonarakis SE, McInnis MG, et al. (July 1995). "Characterization of cDNA clones containing CCA trinucleotide repeats derived from human brain". Somatic Cell and Molecular Genetics. 21 (4): 279–284. doi:10.1007/BF02255782. PMID 8525433. S2CID 22174220.
- Ohnishi H, Kubota M, Ohtake A, Sato K, Sano S (October 1996). "Activation of protein-tyrosine phosphatase SH-PTP2 by a tyrosine-based activation motif of a novel brain molecule". The Journal of Biological Chemistry. 271 (41): 25569–25574. doi:10.1074/jbc.271.41.25569 . PMID 8810330.
- Fujioka Y, Matozaki T, Noguchi T, Iwamatsu A, Yamao T, Takahashi N, et al. (December 1996). "A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion". Molecular and Cellular Biology. 16 (12): 6887–6899. doi:10.1128/MCB.16.12.6887. PMC 231692 . PMID 8943344.
- Sano S, Ohnishi H, Omori A, Hasegawa J, Kubota M (July 1997). "BIT, an immune antigen receptor-like molecule in the brain". FEBS Letters. 411 (2–3): 327–334. doi:10.1016/S0014-5793(97)00724-2 . PMID 9271230. S2CID 39554802.
- Brooke GP, Parsons KR, Howard CJ (January 1998). "Cloning of two members of the SIRP alpha family of protein tyrosine phosphatase binding proteins in cattle that are expressed on monocytes and a subpopulation of dendritic cells and which mediate binding to CD4 T cells". European Journal of Immunology. 28 (1): 1–11. doi:10.1002/(SICI)1521-4141(199801)28:01<1::AID-IMMU1>3.0.CO;2-V . PMID 9485180.
- Timms JF, Carlberg K, Gu H, Chen H, Kamatkar S, Nadler MJ, et al. (July 1998). "Identification of major binding proteins and substrates for the SH2-containing protein tyrosine phosphatase SHP-1 in macrophages". Molecular and Cellular Biology. 18 (7): 3838–3850. doi:10.1128/mcb.18.7.3838. PMC 108968 . PMID 9632768.
- Veillette A, Thibaudeau E, Latour S (August 1998). "High expression of inhibitory receptor SHPS-1 and its association with protein-tyrosine phosphatase SHP-1 in macrophages". The Journal of Biological Chemistry. 273 (35): 22719–22728. doi:10.1074/jbc.273.35.22719 . PMID 9712903.
- Jiang P, Lagenaur CF, Narayanan V (January 1999). "Integrin-associated protein is a ligand for the P84 neural adhesion molecule". The Journal of Biological Chemistry. 274 (2): 559–562. doi:10.1074/jbc.274.2.559 . PMID 9872987.
- Ohnishi H, Yamada M, Kubota M, Hatanaka H, Sano S (April 1999). "Tyrosine phosphorylation and association of BIT with SHP-2 induced by neurotrophins". Journal of Neurochemistry. 72 (4): 1402–1408. doi:10.1046/j.1471-4159.1999.721402.x . PMID 10098842. S2CID 83600875.
- Timms JF, Swanson KD, Marie-Cardine A, Raab M, Rudd CE, Schraven B, et al. (August 1999). "SHPS-1 is a scaffold for assembling distinct adhesion-regulated multi-protein complexes in macrophages". Current Biology. 9 (16): 927–930. Bibcode:1999CBio....9..927T. doi:10.1016/S0960-9822(99)80401-1 . PMID 10469599. S2CID 16056124.
- Seiffert M, Cant C, Chen Z, Rappold I, Brugger W, Kanz L, et al. (December 1999). "Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving its counterreceptor CD47". Blood. 94 (11): 3633–3643. doi:10.1182/blood.V94.11.3633. PMID 10572074. S2CID 11033417.
- Sano S, Ohnishi H, Kubota M (December 1999). "Gene structure of mouse BIT/SHPS-1". The Biochemical Journal. 344 (Pt 3): 667–675. doi:10.1042/0264-6021:3440667. PMC 1220688 . PMID 10585853.
- Yang J, Cheng Z, Niu T, Liang X, Zhao ZJ, Zhou GW (February 2000). "Structural basis for substrate specificity of protein-tyrosine phosphatase SHP-1". The Journal of Biological Chemistry. 275 (6): 4066–4071. doi:10.1074/jbc.275.6.4066 . PMID 10660565.
- Stofega MR, Argetsinger LS, Wang H, Ullrich A, Carter-Su C (September 2000). "Negative regulation of growth hormone receptor/JAK2 signaling by signal regulatory protein alpha". The Journal of Biological Chemistry. 275 (36): 28222–28229. doi:10.1074/jbc.M004238200 . PMID 10842184.
- Wu CJ, Chen Z, Ullrich A, Greene MI, O'Rourke DM (August 2000). "Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by signal-regulatory proteins (SIRPs)". Oncogene. 19 (35): 3999–4010. doi:10.1038/sj.onc.1203748. PMID 10962556. S2CID 9020984.
- Latour S, Tanaka H, Demeure C, Mateo V, Rubio M, Brown EJ, et al. (September 2001). "Bidirectional negative regulation of human T and dendritic cells by CD47 and its cognate receptor signal-regulator protein-alpha: down-regulation of IL-12 responsiveness and inhibition of dendritic cell activation". Journal of Immunology. 167 (5): 2547–2554. doi:10.4049/jimmunol.167.5.2547 . PMID 11509594.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.