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Role of SRC-like adaptor protein (SLAP) in immune and malignant cell signaling

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Abstract

SRC-like adaptor protein (SLAP) is an adaptor protein structurally similar to the SRC family protein kinases. Like SRC, SLAP contains an SH3 domain followed by an SH2 domain but the kinase domain has been replaced by a unique C-terminal region. SLAP is expressed in a variety of cell types. Current studies suggest that it regulates signaling of various cell surface receptors including the B cell receptor, the T cell receptor, cytokine receptors and receptor tyrosine kinases which are important regulator of immune and cancer cell signaling. SLAP targets receptors, or its associated components, by recruiting the ubiquitin machinery and thereby destabilizing signaling. SLAP directs receptors to ubiquitination-mediated degradation and controls receptors turnover as well as signaling. Thus, SLAP appears to be an important component in regulating signal transduction required for immune and malignant cells.

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References

  1. Roche S, Alonso G, Kazlauskas A, Dixit VM, Courtneidge SA, Pandey A (1998) Src-like adaptor protein (Slap) is a negative regulator of mitogenesis. Curr Biol 8:975–978. doi:10.1016/S0960-9822(98)70400-2

    Article  CAS  PubMed  Google Scholar 

  2. Sosinowski T, Killeen N, Weiss A (2001) The Src-like adaptor protein downregulates the T cell receptor on CD4+ CD8+ thymocytes and regulates positive selection. Immunity 15:457–466. doi:10.1016/S1074-7613(01)00195-9

    Article  CAS  PubMed  Google Scholar 

  3. Kim HJ, Zou W, Ito Y et al (2010) Src-like adaptor protein regulates osteoclast generation and survival. J Cell Biochem 110:201–209. doi:10.1002/jcb.22527

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Friend SF, Peterson LK, Kedl RM, Dragone LL (2013) SLAP deficiency increases TCR avidity leading to altered repertoire and negative selection of cognate antigen-specific CD8+ T cells. Immunol Res 55:116–124. doi:10.1007/s12026-012-8354-y

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Dragone LL, Shaw LA, Myers MD, Weiss A (2009) SLAP, a regulator of immunoreceptor ubiquitination, signaling, and trafficking. Immunol Rev 232:218–228. doi:10.1111/j.1600-065X.2009.00827.x

    Article  CAS  PubMed  Google Scholar 

  6. Pandey A, Duan H, Dixit VM (1995) Characterization of a novel Src-like adapter protein that associates with the Eck receptor tyrosine kinase. J Biol Chem 270:19201–19204

    Article  CAS  PubMed  Google Scholar 

  7. Angrist M, Wells DE, Chakravarti A, Pandey A (1995) Chromosomal localization of the mouse Src-like adapter protein (Slap) gene and its putative human homolog SLA. Genomics 30:623–625. doi:10.1006/geno.1995.1289

    Article  CAS  PubMed  Google Scholar 

  8. Kratchmarova I, Sosinowski T, Weiss A, Witter K, Vincenz C, Pandey A (2001) Characterization of promoter region and genomic structure of the murine and human genes encoding Src like adapter protein. Gene 262:267–273. doi:10.1016/S0378-1119(00)00516-3

    Article  CAS  PubMed  Google Scholar 

  9. Meijerink PH, Yanakiev P, Zorn I et al (1998) The gene for the human Src-like adaptor protein (hSLAP) is located within the 64-kb intron of the thyroglobulin gene. Eur J Biochem 254:297–303. doi:10.1046/j.1432-1327.1998.2540297.x

    Article  CAS  PubMed  Google Scholar 

  10. Holland SJ, Liao XC, Mendenhall MK et al (2001) Functional cloning of Src-like adapter protein-2 (SLAP-2), a novel inhibitor of antigen receptor signaling. J Exp Med 194:1263–1276

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Pandey A, Ibarrola N, Kratchmarova I et al (2002) A novel Src homology 2 domain-containing molecule, Src-like adapter protein-2 (SLAP-2), which negatively regulates T cell receptor signaling. J Biol Chem 277:19131–19138. doi:10.1074/jbc.M110318200

    Article  CAS  PubMed  Google Scholar 

  12. Loreto MP, McGlade CJ (2003) Cloning and characterization of human Src-like adaptor protein 2 and a novel splice isoform, SLAP-2-v. Oncogene 22:266–273. doi:10.1038/sj.onc.1206114

    Article  CAS  PubMed  Google Scholar 

  13. Sosinowski T, Pandey A, Dixit VM, Weiss A (2000) Src-like adaptor protein (SLAP) is a negative regulator of T cell receptor signaling. J Exp Med 191:463–474

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Tang J, Sawasdikosol S, Chang JH, Burakoff SJ (1999) SLAP, a dimeric adapter protein, plays a functional role in T cell receptor signaling. Proc Natl Acad Sci USA 96:9775–9780. doi:10.1073/pnas.96.17.9775

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Ohtsuki T, Hatake K, Ikeda M et al (1997) Expression of Src-like adapter protein mRNA is induced by all-trans retinoic acid. Biochem Biophys Res Commun 230:81–84. doi:10.1006/bbrc.1996.5887

    Article  CAS  PubMed  Google Scholar 

  16. Hiragun T, Peng Z, Beaven MA (2006) Cutting edge: dexamethasone negatively regulates Syk in mast cells by up-regulating SRC-like adaptor protein. J Immunol 177:2047–2050. doi:10.4049/jimmunol.177.4.2047

    Article  CAS  PubMed  Google Scholar 

  17. Park SK, Beaven MA (2009) Mechanism of upregulation of the inhibitory regulator, src-like adaptor protein (SLAP), by glucocorticoids in mast cells. Mol Immunol 46:492–497. doi:10.1016/j.molimm.2008.10.011

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Mansha M, Carlet M, Ploner C et al (2010) Functional analyses of Src-like adaptor (SLA), a glucocorticoid-regulated gene in acute lymphoblastic leukemia. Leukoc Res 34:529–534. doi:10.1016/j.leukres.2009.06.029

    Article  CAS  Google Scholar 

  19. Loreto MP, Berry DM, McGlade CJ (2002) Functional cooperation between c-Cbl and Src-like adaptor protein 2 in the negative regulation of T-cell receptor signaling. Mol Cell Biol 22:4241–4255

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Sugihara S, Katsutani S, Deckmyn H, Fujimura K, Kimura A (2010) Roles of Src-like adaptor protein 2 (SLAP-2) in GPVI-mediated platelet activation SLAP-2 and GPVI signaling. Thromb Res 126:e276–e285. doi:10.1016/j.thromres.2010.07.010

    Article  CAS  PubMed  Google Scholar 

  21. Manes G, Bello P, Roche S (2000) Slap negatively regulates Src mitogenic function but does not revert Src-induced cell morphology changes. Mol Cell Biol 20:3396–3406. doi:10.1128/MCB.20.10.3396-3406.2000

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Kazi JU, Rönnstrand L (2012) Src-Like adaptor protein (SLAP) binds to the receptor tyrosine kinase Flt3 and modulates receptor stability and downstream signaling. PLoS ONE 7:e53509. doi:10.1371/journal.pone.0053509

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Kazi JU, Agarwal S, Sun J, Bracco E, Rönnstrand L (2014) Src-like-adaptor protein (SLAP) differentially regulates normal and oncogenic c-Kit signaling. J Cell Sci 127:653–662. doi:10.1242/jcs.140590

    Article  CAS  PubMed  Google Scholar 

  24. Lebigot I, Gardellin P, Lefebvre L, Beug H, Ghysdael J, Quang CT (2003) Up-regulation of SLAP in FLI-1-transformed erythroblasts interferes with EpoR signaling. Blood 102:4555–4562. doi:10.1182/blood-2003-06-2077

    Article  CAS  PubMed  Google Scholar 

  25. Kazi JU, Kabir NN, Flores-Morales A, Rönnstrand L (2014) SOCS proteins in regulation of receptor tyrosine kinase signaling. Cell Mol Life Sci 71:3297–3310. doi:10.1007/s00018-014-1619-y

    Article  CAS  PubMed  Google Scholar 

  26. Kabir NN, Sun J, Rönnstrand L, Kazi JU (2014) SOCS6 is a selective suppressor of receptor tyrosine kinase signaling. Tumour Biol. doi:10.1007/s13277-014-2542-4

    PubMed  Google Scholar 

  27. Kabir NN, Kazi JU (2014) Grb10 is a dual regulator of receptor tyrosine kinase signaling. Mol Biol Rep 41:1985–1992. doi:10.1007/s11033-014-3046-4

    Article  CAS  PubMed  Google Scholar 

  28. Lennartsson J, Rönnstrand L (2012) Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev 92:1619–1649. doi:10.1152/physrev.00046.2011

    Article  CAS  PubMed  Google Scholar 

  29. Dragone LL, Myers MD, White C et al (2006) Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent manner. Proc Natl Acad Sci USA 103:18202–18207. doi:10.1073/pnas.0608965103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Fu G, Rybakin V, Brzostek J, Paster W, Acuto O, Gascoigne NR (2014) Fine-tuning T cell receptor signaling to control T cell development. Trends Immunol 35:311–318. doi:10.1016/j.it.2014.05.003

    Article  CAS  PubMed  Google Scholar 

  31. Ersek B, Molnar V, Balogh A et al (2012) CD3zeta-chain expression of human T lymphocytes is regulated by TNF via Src-like adaptor protein-dependent proteasomal degradation. J Immunol 189:1602–1610. doi:10.4049/jimmunol.1102365

    Article  CAS  PubMed  Google Scholar 

  32. Myers MD, Dragone LL, Weiss A (2005) Src-like adaptor protein down-regulates T cell receptor (TCR)-CD3 expression by targeting TCRzeta for degradation. J Cell Biol 170:285–294. doi:10.1083/jcb.200501164

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Myers MD, Sosinowski T, Dragone LL et al (2006) Src-like adaptor protein regulates TCR expression on thymocytes by linking the ubiquitin ligase c-Cbl to the TCR complex. Nat Immunol 7:57–66. doi:10.1038/ni1291

    Article  CAS  PubMed  Google Scholar 

  34. Kazi JU, Kabir NN, Rönnstrand L (2013) Protein kinase C (PKC) as a drug target in chronic lymphocytic leukemia. Med Oncol 30:757. doi:10.1007/s12032-013-0757-7

    Article  PubMed  Google Scholar 

  35. Kazi JU (2011) The mechanism of protein kinase C regulation. Front Biol 6:328–336. doi:10.1007/s11515-011-1070-5

    CAS  Google Scholar 

  36. Kurosaki T (2011) Regulation of BCR signaling. Mol Immunol 48:1287–1291. doi:10.1016/j.molimm.2010.12.007

    Article  CAS  PubMed  Google Scholar 

  37. Dragone LL, Myers MD, White C, Sosinowski T, Weiss A (2006) SRC-like adaptor protein regulates B cell development and function. J Immunol 176:335–345. doi:10.4049/jimmunol.176.1.335

    Article  CAS  PubMed  Google Scholar 

  38. Peterson LK, Pennington LF, Shaw LA et al (2014) SLAP deficiency decreases dsDNA autoantibody production. Clin Immunol 150:201–209. doi:10.1016/j.clim.2013.12.007

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Kagaya Y, Asaumi Y, Wang W et al (2012) Current perspectives on protective roles of erythropoietin in cardiovascular system: erythropoietin receptor as a novel therapeutic target. Tohoku J Exp Med 227:83–91. doi:10.1620/tjem.227.83

    Article  CAS  PubMed  Google Scholar 

  40. Munugalavadla V, Kapur R (2005) Role of c-Kit and erythropoietin receptor in erythropoiesis. Crit Rev Oncol Hematol 54:63–75. doi:10.1016/j.critrevonc.2004.11.005

    Article  PubMed  Google Scholar 

  41. Liontos LM, Dissanayake D, Ohashi PS, Weiss A, Dragone LL, McGlade CJ (2011) The Src-like adaptor protein regulates GM-CSFR signaling and monocytic dendritic cell maturation. J Immunol 186:1923–1933. doi:10.4049/jimmunol.0903292

    Article  CAS  PubMed  Google Scholar 

  42. Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179–185. doi:10.1016/0092-8674(95)90401-8

    Article  CAS  PubMed  Google Scholar 

  43. Semerdjieva S, Abdul-Razak HH, Salim SS et al (2013) Activation of EphA receptors mediates the recruitment of the adaptor protein Slap, contributing to the downregulation of N-methyl-d-aspartate receptors. Mol Cell Biol 33:1442–1455. doi:10.1128/MCB.01618-12

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Naudin C, Sirvent A, Leroy C et al (2014) SLAP displays tumour suppressor functions in colorectal cancer via destabilization of the SRC substrate EPHA2. Nat Commun 5:3159. doi:10.1038/ncomms4159

    Article  PubMed  Google Scholar 

  45. Sirvent A, Leroy C, Boureux A, Simon V, Roche S (2008) The Src-like adaptor protein regulates PDGF-induced actin dorsal ruffles in a c-Cbl-dependent manner. Oncogene 27:3494–3500. doi:10.1038/sj.onc.1211011

    Article  CAS  PubMed  Google Scholar 

  46. Manes GA, Masendycz P, Nguyen T et al (2006) A potential role for the Src-like adapter protein SLAP-2 in signaling by the colony stimulating factor-1 receptor. FEBS J 273:1791–1804. doi:10.1111/j.1742-4658.2006.05199.x

    Article  CAS  PubMed  Google Scholar 

  47. Pakuts B, Debonneville C, Liontos LM, Loreto MP, McGlade CJ (2007) The Src-like adaptor protein 2 regulates colony-stimulating factor-1 receptor signaling and down-regulation. J Biol Chem 282:17953–17963. doi:10.1074/jbc.M701182200

    Article  CAS  PubMed  Google Scholar 

  48. Park SK, Qiao H, Beaven MA (2009) Src-like adaptor protein (SLAP) is upregulated in antigen-stimulated mast cells and acts as a negative regulator. Mol Immunol 46:2133–2139. doi:10.1016/j.molimm.2009.03.013

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

This research was funded by Kungliga Fysiografiska Sällskapet i Lund (JUK), Ollie and Elof Ericssons Stiftelse (JUK), Åke-Wiberg Stiftelse (JUK), Lars Hiertas Minne Stiftelse (JUK), Stiftelsen Olle Engkvist Byggmästare (JUK), Harald Jeanssons Stiftelse and Harald och Greta Jeanssons Stiftelse (JUK), Swedish Childhood Cancer Foundation (JUK), Gunnar Nilsson Cancer Foundation (LR), Swedish Cancer Society (LR), BioCARE cancer network (LR and JUK) and the Swedish Research Council (LR). JUK is a recipient of Assistant Professorship (forskarassistenttjänst) grant from the Swedish Childhood Cancer Foundation.

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Authors and Affiliations

  1. Division of Translational Cancer Research, Lund University, Medicon Village 404:C3, 223 63, Lund, Sweden

    Julhash U. Kazi & Lars Rönnstrand

  2. Lund Stem Cell Center, Lund University, Lund, Sweden

    Julhash U. Kazi & Lars Rönnstrand

  3. Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh

    Julhash U. Kazi & Nuzhat N. Kabir

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  1. Julhash U. Kazi
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  2. Nuzhat N. Kabir
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  3. Lars Rönnstrand
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Correspondence to Lars Rönnstrand.

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Kazi, J.U., Kabir, N.N. & Rönnstrand, L. Role of SRC-like adaptor protein (SLAP) in immune and malignant cell signaling. Cell. Mol. Life Sci. 72, 2535–2544 (2015). https://doi.org/10.1007/s00018-015-1882-6

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