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Gene Review

LCP2  -  lymphocyte cytosolic protein 2 (SH2 domain...

Homo sapiens

Synonyms: Lymphocyte cytosolic protein 2, SH2 domain-containing leukocyte protein of 76 kDa, SLP-76, SLP-76 tyrosine phosphoprotein, SLP76
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Disease relevance of LCP2


High impact information on LCP2


Chemical compound and disease context of LCP2


Biological context of LCP2


Anatomical context of LCP2


Associations of LCP2 with chemical compounds

  • The data indicate that TCR-mediated ROS generation leads to SHP-2 oxidation, which promotes T-cell adhesion through effects on an SLP-76-dependent signaling pathway to integrin activation [18].
  • Here we report that the serine/threonine kinase hematopoietic progenitor kinase 1 (HPK1), which is activated upon antigen-receptor stimulation and which has been implicated in the regulation of MAP kinase pathways, interacts physically and functionally with BLNK in B cells and with SLP-76 in T cells [11].
  • In vitro experiments show that the SH2 domain of SLP-76 associates with the 62- and 130-kD proteins and additionally with a serine/threonine kinase [19].
  • SH2 domain-containing protein 76 (SLP-76) interacts with the guanine nucleotide exchange factor Vav to activate the nuclear factor of activated cells (NF-AT), and its expression is required for normal T cell development [20].
  • Additional deletion mutations revealed a new, 67-amino-acid functional domain within the proline-rich region of SLP-76, which we have termed the P-1 domain [21].

Physical interactions of LCP2

  • FYB/SLAP has the hallmarks of an adaptor protein that binds to the SH2 domains of the Src kinase FYN-T and SLP-76 [22].
  • We find the Gads binding domain and the P1 domain are both necessary for optimal SLP-76 function, and in the absence of these two regions, SLP-76 is functionally inert [23].
  • Grb2 and Cbl binding to SLP-76 were inducible after Fc gammaRI stimulation of the macrophages [24].
  • CD28 signaling is dependent on VAV/SLP-76 complex formation and induces membrane localization of these complexes [25].
  • 14-3-3 epsilon and 14-3-3 zeta proteins are SLP-76 binding partners. These interaction are induced by TCR ligation and require phosphorylation of SLP-76 at serine 376.[26]

Enzymatic interactions of LCP2

  • Moreover, SLP-76 is preferentially phosphorylated by ZAP-70 in vitro and in heterologous cellular systems [27].
  • Serine 376 of SLP-76 is phosphorylated by the hematopoietic progenitor kinase 1 (HPK-1) [26].

Regulatory relationships of LCP2

  • RESULTS: We found that Gads is highly expressed in T cells and that the SLP-76 adaptor protein is a major Gads-associated protein in vivo [28].
  • These results establish a novel physical link between Vav and SLP-76 that is differentially regulated by CD45 isoform expression [29].
  • Phosphorylation of SLP-76 is diminished in T cells that express a catalytically inactive ZAP-70 [27].
  • Finally, we demonstrate that transient overexpression of SLP-76 results in dramatically enhanced TCR-mediated induction of nuclear factor of activated T cells (NFAT) and interleukin (IL) 2 promoter activity; and we provide evidence that a functional SLP-76 SH2 domain is required for this effect [19].
  • These findings document the existence of a T-cell receptor-regulated FYN-T-FYB pathway that interfaces with the adaptor SLP-76 and up-regulates lymphokine production in T-cells [30].

Other interactions of LCP2

  • Hence, these data suggest a functional overlap between BLNK and SLP-76, while emphasizing the difference in requirement for additional adaptor molecules in their targeting to GEMs [14].
  • Gads may promote cross-talk between the LAT and SLP-76 signaling complexes, thereby coupling membrane-proximal events to downstream signaling pathways [28].
  • This pathway involves ZAP-70-dependent tyrosine phosphorylation of SLP-76 at one or more of its tyrosines, 113, 128, and 145 [31].
  • In contrast, replenishment of SLP-76 or PLCgamma1 expression restored CD3/CD28-induced IkappaB kinase (IKK) activity as well as NF-kappaB DNA binding and transactivation [1].
  • PKCtheta activated NF-kappaB in SLP-76- and PLCgamma1-deficient cells, showing that PKCtheta is acting further downstream [1].

Analytical, diagnostic and therapeutic context of LCP2




  1. Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa and phospholipase C gamma 1 are required for NF-kappa B activation and lipid raft recruitment of protein kinase C theta induced by T cell costimulation. Dienz, O., Möller, A., Strecker, A., Stephan, N., Krammer, P.H., Dröge, W., Schmitz, M.L. J. Immunol. (2003) [Pubmed]
  2. The adaptor molecules LAT and SLP-76 are specifically targeted by Yersinia to inhibit T cell activation. Gerke, C., Falkow, S., Chien, Y.H. J. Exp. Med. (2005) [Pubmed]
  3. Intracellular signalling molecules as immunohistochemical markers of normal and neoplastic human leucocytes in routine biopsy samples. Pozzobon, M., Marafioti, T., Hansmann, M.L., Natkunam, Y., Mason, D.Y. Br. J. Haematol. (2004) [Pubmed]
  4. Protein-tyrosine kinases and adaptor proteins in FcepsilonRI-mediated signaling in mast cells. Sada, K., Yamamura, H. Curr. Mol. Med. (2003) [Pubmed]
  5. Loss of SLP-76 Expression within Myeloid Cells Confers Resistance to Neutrophil-Mediated Tissue Damage while Maintaining Effective Bacterial Killing. Clemens, R.A., Lenox, L.E., Kambayashi, T., Bezman, N., Maltzman, J.S., Nichols, K.E., Koretzky, G.A. J. Immunol. (2007) [Pubmed]
  6. Mechanisms of signaling by the hematopoietic-specific adaptor proteins, SLP-76 and LAT and their B cell counterpart, BLNK/SLP-65. Yablonski, D., Weiss, A. Adv. Immunol. (2001) [Pubmed]
  7. Uncoupling of nonreceptor tyrosine kinases from PLC-gamma1 in an SLP-76-deficient T cell. Yablonski, D., Kuhne, M.R., Kadlecek, T., Weiss, A. Science (1998) [Pubmed]
  8. Trichostatin A down-regulates ZAP-70, LAT and SLP-76 content in Jurkat T cells. Januchowski, R., Jagodzinski, P.P. Int. Immunopharmacol. (2007) [Pubmed]
  9. Polymorphism in and localization of the gene LCP2 (SLP-76) to chromosome 5q33.1-qter. Sunden, S.L., Carr, L.L., Clements, J.L., Motto, D.G., Koretzky, G.A. Genomics (1996) [Pubmed]
  10. Dynamic molecular interactions linking the T cell antigen receptor to the actin cytoskeleton. Barda-Saad, M., Braiman, A., Titerence, R., Bunnell, S.C., Barr, V.A., Samelson, L.E. Nat. Immunol. (2005) [Pubmed]
  11. Hematopoietic progenitor kinase 1 associates physically and functionally with the adaptor proteins B cell linker protein and SLP-76 in lymphocytes. Sauer, K., Liou, J., Singh, S.B., Yablonski, D., Weiss, A., Perlmutter, R.M. J. Biol. Chem. (2001) [Pubmed]
  12. Resting lymphocyte kinase (Rlk/Txk) targets lymphoid adaptor SLP-76 in the cooperative activation of interleukin-2 transcription in T-cells. Schneider, H., Guerette, B., Guntermann, C., Rudd, C.E. J. Biol. Chem. (2000) [Pubmed]
  13. Membrane localization and function of Vav3 in T cells depend on its association with the adapter SLP-76. Charvet, C., Canonigo, A.J., Billadeau, D.D., Altman, A. J. Biol. Chem. (2005) [Pubmed]
  14. Involvement of LAT, Gads, and Grb2 in compartmentation of SLP-76 to the plasma membrane. Ishiai, M., Kurosaki, M., Inabe, K., Chan, A.C., Sugamura, K., Kurosaki, T. J. Exp. Med. (2000) [Pubmed]
  15. Fyn-binding protein (Fyb)/SLP-76-associated protein (SLAP), Ena/vasodilator-stimulated phosphoprotein (VASP) proteins and the Arp2/3 complex link T cell receptor (TCR) signaling to the actin cytoskeleton. Krause, M., Sechi, A.S., Konradt, M., Monner, D., Gertler, F.B., Wehland, J. J. Cell Biol. (2000) [Pubmed]
  16. PRAM-1 is a novel adaptor protein regulated by retinoic acid (RA) and promyelocytic leukemia (PML)-RA receptor alpha in acute promyelocytic leukemia cells. Moog-Lutz, C., Peterson, E.J., Lutz, P.G., Eliason, S., Cavé-Riant, F., Singer, A., Di Gioia, Y., Dmowski, S., Kamens, J., Cayre, Y.E., Koretzky, G. J. Biol. Chem. (2001) [Pubmed]
  17. The molecular adapter SLP-76 relays signals from platelet integrin alphaIIbbeta3 to the actin cytoskeleton. Obergfell, A., Judd, B.A., del Pozo, M.A., Schwartz, M.A., Koretzky, G.A., Shattil, S.J. J. Biol. Chem. (2001) [Pubmed]
  18. Receptor-stimulated oxidation of SHP-2 promotes T-cell adhesion through SLP-76-ADAP. Kwon, J., Qu, C.K., Maeng, J.S., Falahati, R., Lee, C., Williams, M.S. EMBO J. (2005) [Pubmed]
  19. Implication of the GRB2-associated phosphoprotein SLP-76 in T cell receptor-mediated interleukin 2 production. Motto, D.G., Ross, S.E., Wu, J., Hendricks-Taylor, L.R., Koretzky, G.A. J. Exp. Med. (1996) [Pubmed]
  20. GrpL, a Grb2-related adaptor protein, interacts with SLP-76 to regulate nuclear factor of activated T cell activation. Law, C.L., Ewings, M.K., Chaudhary, P.M., Solow, S.A., Yun, T.J., Marshall, A.J., Hood, L., Clark, E.A. J. Exp. Med. (1999) [Pubmed]
  21. Identification of a phospholipase C-gamma1 (PLC-gamma1) SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-gamma1 and NFAT. Yablonski, D., Kadlecek, T., Weiss, A. Mol. Cell. Biol. (2001) [Pubmed]
  22. Novel isoform of lymphoid adaptor FYN-T-binding protein (FYB-130) interacts with SLP-76 and up-regulates interleukin 2 production. Veale, M., Raab, M., Li, Z., da Silva, A.J., Kraeft, S.K., Weremowicz, S., Morton, C.C., Rudd, C.E. J. Biol. Chem. (1999) [Pubmed]
  23. Roles of the proline-rich domain in SLP-76 subcellular localization and T cell function. Singer, A.L., Bunnell, S.C., Obstfeld, A.E., Jordan, M.S., Wu, J.N., Myung, P.S., Samelson, L.E., Koretzky, G.A. J. Biol. Chem. (2004) [Pubmed]
  24. Cbl functions downstream of Src kinases in Fc gamma RI signaling in primary human macrophages. Erdreich-Epstein, A., Liu, M., Kant, A.M., Izadi, K.D., Nolta, J.A., Durden, D.L. J. Leukoc. Biol. (1999) [Pubmed]
  25. CD28 signaling via VAV/SLP-76 adaptors: regulation of cytokine transcription independent of TCR ligation. Raab, M., Pfister, S., Rudd, C.E. Immunity (2001) [Pubmed]
  26. A novel pathway down-modulating T cell activation involves HPK-1-dependent recruitment of 14-3-3 proteins on SLP-76. Di Bartolo, V., Montagne, B., Salek, M., Jungwirth, B., Carrette, F., Fourtane, J., Sol-Foulon, N., Michel, F., Schwartz, O., Lehmann, W.D., Acuto, O. J. Exp. Med. (2007) [Pubmed]
  27. Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. Wardenburg, J.B., Fu, C., Jackman, J.K., Flotow, H., Wilkinson, S.E., Williams, D.H., Johnson, R., Kong, G., Chan, A.C., Findell, P.R. J. Biol. Chem. (1996) [Pubmed]
  28. The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. Liu, S.K., Fang, N., Koretzky, G.A., McGlade, C.J. Curr. Biol. (1999) [Pubmed]
  29. Differential regulation of activation-induced tyrosine phosphorylation and recruitment of SLP-76 to Vav by distinct isoforms of the CD45 protein-tyrosine phosphatase. Onodera, H., Motto, D.G., Koretzky, G.A., Rothstein, D.M. J. Biol. Chem. (1996) [Pubmed]
  30. FYN-T-FYB-SLP-76 interactions define a T-cell receptor zeta/CD3-mediated tyrosine phosphorylation pathway that up-regulates interleukin 2 transcription in T-cells. Raab, M., Kang, H., da Silva, A., Zhu, X., Rudd, C.E. J. Biol. Chem. (1999) [Pubmed]
  31. Distinct role of ZAP-70 and Src homology 2 domain-containing leukocyte protein of 76 kDa in the prolonged activation of extracellular signal-regulated protein kinase by the stromal cell-derived factor-1 alpha/CXCL12 chemokine. Kremer, K.N., Humphreys, T.D., Kumar, A., Qian, N.X., Hedin, K.E. J. Immunol. (2003) [Pubmed]
  32. Molecular cloning of three cDNAs that encode cysteine proteinases in the digestive gland of the American lobster (Homarus americanus). Laycock, M.V., MacKay, R.M., Di Fruscio, M., Gallant, J.W. FEBS Lett. (1991) [Pubmed]
  33. Molecular cloning of SLP-76, a 76-kDa tyrosine phosphoprotein associated with Grb2 in T cells. Jackman, J.K., Motto, D.G., Sun, Q., Tanemoto, M., Turck, C.W., Peltz, G.A., Koretzky, G.A., Findell, P.R. J. Biol. Chem. (1995) [Pubmed]
  34. Association of the Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) with the p85 subunit of phosphoinositide 3-kinase. Shim, E.K., Moon, C.S., Lee, G.Y., Ha, Y.J., Chae, S.K., Lee, J.R. FEBS Lett. (2004) [Pubmed]
  35. Structural basis for recognition of the T cell adaptor protein SLP-76 by the SH3 domain of phospholipase Cgamma1. Deng, L., Velikovsky, C.A., Swaminathan, C.P., Cho, S., Mariuzza, R.A. J. Mol. Biol. (2005) [Pubmed]
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