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Gene Review

Lcp2  -  lymphocyte cytosolic protein 2

Mus musculus

Synonyms: AI323664, BB161688, Lymphocyte cytosolic protein 2, SH2 domain-containing leukocyte protein of 76 kDa, SLP-76, ...
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Disease relevance of Lcp2

  • Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice [1].
  • SLP-76(-/-) mice are resistant to IgE-mediated passive anaphylaxis [2].
  • SLP-76(-/-) mice sensitized with IgE anti-dinitrophenyl (DNP) and then challenged with DNP-HSA developed only mild and transient tachycardia, failed to increase their plasma histamine level, and all survived the antigen challenge [2].
  • To determine whether macrophages functioned normally in vivo, we infected WT and SLP-76(-/-) SLP-65(-/-) mice with sublethal doses of Listeria monocytogenes (LM), a bacterium against which the initial host defense is provided by activated macrophages [3].
  • Despite these abnormalities, SLP-76-deficient neutrophils migrated normally in vivo in response to Staphylococcus aureus infection and efficiently cleared micro-organisms [4].

High impact information on Lcp2


Biological context of Lcp2


Anatomical context of Lcp2

  • SLP-76-deficient mice show a high frequency of neonatal lethality; and in surviving mice, T cell development is blocked at the DN3 stage [10].
  • Macrophage and natural killer cell compartments were intact in SLP-76-deficient mice, despite SLP-76 expression in these lineages in wild-type mice [7].
  • Bone marrow-derived mast cells (BMMCs) from SLP76(-/-) mice failed to release beta-hexosaminidase and to secrete IL-6 after FcepsilonRI cross-linking [2].
  • We show that murine bone marrow-derived macrophages express both SLP-76 and BLNK [11].
  • The in vivo bleeding diathesis as well as the defects in platelet responses to fibrinogen and collagen are reversed by retroviral transduction of SLP-76 into bone marrow derived from SLP-76-deficient mice [9].

Associations of Lcp2 with chemical compounds

  • This differs from mice lacking the tyrosine kinase Syk that is upstream of BLNK in BCR signaling and contrasts with mice lacking SLP-76 that is the equivalent adaptor molecule in TCR-signal transduction [12].
  • In contrast, SLP-76-deficient murine platelets bind fibrinogen normally, but spread poorly and exhibit reduced levels of phosphotyrosine [9].
  • We found that the N-terminal tyrosines as well as the central proline-rich region of SLP-76 are required for participation of SLP-76 in FcepsilonRI-mediated signaling and function [13].
  • With the involvement of Syk, SLP-76, and Btk, alphaIIbbeta3-induced PLCgamma2 activation partly overlaps with the pathway used by the collagen receptor glycoprotein VI [14].
  • Here we demonstrate a critical role for the adaptor molecule SH2 domain-containing leukoctye-specific phosphoprotein of 76 kDa (SLP-76) in FcgammaR and integrin signaling [15].

Physical interactions of Lcp2

  • We further demonstrated that the expression of the Gads-binding region of SLP-76 in bone marrow-derived mast cells inhibits FcepsilonRI-induced calcium flux, degranulation, and cytokine secretion [16].
  • SLP-76(-/-) platelets also exhibited less annexin V binding than SLP-76(+/-) platelets after costimulation with thrombin and convulxin (P <.05) [17].

Enzymatic interactions of Lcp2

  • At this time, ZAP-70 from both normal and c-Cbl-/- thymocytes becomes hyperphosphorylated; however, only in normal thymocytes does this correlate with ZAP-70 down-regulation and a diminished ability to phosphorylate LAT and SLP-76 [18].

Regulatory relationships of Lcp2


Other interactions of Lcp2

  • Inactivation of c-cbl completely reversed the neonatal lethality seen in SLP-76-deficient mice and partially reversed the T cell development arrest in these mice [10].
  • Together, our results suggest that the adaptor proteins LAT and SLP-76 are involved in pre-BCR signaling, thereby rescuing arrested murine SLP-65(-/-) pre-B cells [21].
  • Expression of an SH2 domain-containing COOH-terminal fragment of Vav inhibited Vav phosphorylation and movement to the GEMs but had no effect on the tyrosine phosphorylation of the adaptor protein, SLP-76 (SH2 domain-containing leukocyte protein of 76 kD), and LAT [22].
  • Immune functions in mice lacking Clnk, an SLP-76-related adaptor expressed in a subset of immune cells [23].
  • Thus, failure to bind ADAP does not underlie the functional defects exhibited by SLP-76 SH2 domain mutant-expressing mast cells [13].

Analytical, diagnostic and therapeutic context of Lcp2


  1. Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice. Clements, J.L., Lee, J.R., Gross, B., Yang, B., Olson, J.D., Sandra, A., Watson, S.P., Lentz, S.R., Koretzky, G.A. J. Clin. Invest. (1999) [Pubmed]
  2. SLP-76 deficiency impairs signaling via the high-affinity IgE receptor in mast cells. Pivniouk, V.I., Martin, T.R., Lu-Kuo, J.M., Katz, H.R., Oettgen, H.C., Geha, R.S. J. Clin. Invest. (1999) [Pubmed]
  3. Macrophage activation and Fcgamma receptor-mediated signaling do not require expression of the SLP-76 and SLP-65 adaptors. Nichols, K.E., Haines, K., Myung, P.S., Newbrough, S., Myers, E., Jumaa, H., Shedlock, D.J., Shen, H., Koretzky, G.A. J. Leukoc. Biol. (2004) [Pubmed]
  4. 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]
  5. Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76. Pivniouk, V., Tsitsikov, E., Swinton, P., Rathbun, G., Alt, F.W., Geha, R.S. Cell (1998) [Pubmed]
  6. Requirement for the SLP-76 adaptor GADS in T cell development. Yoder, J., Pham, C., Iizuka, Y.M., Kanagawa, O., Liu, S.K., McGlade, J., Cheng, A.M. Science (2001) [Pubmed]
  7. Requirement for the leukocyte-specific adapter protein SLP-76 for normal T cell development. Clements, J.L., Yang, B., Ross-Barta, S.E., Eliason, S.L., Hrstka, R.F., Williamson, R.A., Koretzky, G.A. Science (1998) [Pubmed]
  8. Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell-mediated immune responses. Shui, J.W., Boomer, J.S., Han, J., Xu, J., Dement, G.A., Zhou, G., Tan, T.H. Nat. Immunol. (2007) [Pubmed]
  9. Hematopoietic reconstitution of SLP-76 corrects hemostasis and platelet signaling through alpha IIb beta 3 and collagen receptors. Judd, B.A., Myung, P.S., Leng, L., Obergfell, A., Pear, W.S., Shattil, S.J., Koretzky, G.A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  10. Inactivation of c-Cbl reverses neonatal lethality and T cell developmental arrest of SLP-76-deficient mice. Chiang, Y.J., Sommers, C.L., Jordan, M.S., Gu, H., Samelson, L.E., Koretzky, G.A., Hodes, R.J. J. Exp. Med. (2004) [Pubmed]
  11. Adapter proteins SLP-76 and BLNK both are expressed by murine macrophages and are linked to signaling via Fcgamma receptors I and II/III. Bonilla, F.A., Fujita, R.M., Pivniouk, V.I., Chan, A.C., Geha, R.S. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  12. Cutting edge: B cell linker protein is dispensable for the allelic exclusion of immunoglobulin heavy chain locus but required for the persistence of CD5+ B cells. Xu, S., Wong, S.C., Lam, K.P. J. Immunol. (2000) [Pubmed]
  13. Differential requirement for adapter proteins Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa and adhesion- and degranulation-promoting adapter protein in FcepsilonRI signaling and mast cell function. Wu, J.N., Jordan, M.S., Silverman, M.A., Peterson, E.J., Koretzky, G.A. J. Immunol. (2004) [Pubmed]
  14. A critical role for phospholipase Cgamma2 in alphaIIbbeta3-mediated platelet spreading. Wonerow, P., Pearce, A.C., Vaux, D.J., Watson, S.P. J. Biol. Chem. (2003) [Pubmed]
  15. SLP-76 regulates Fcgamma receptor and integrin signaling in neutrophils. Newbrough, S.A., Mocsai, A., Clemens, R.A., Wu, J.N., Silverman, M.A., Singer, A.L., Lowell, C.A., Koretzky, G.A. Immunity (2003) [Pubmed]
  16. Disruption of SLP-76 interaction with Gads inhibits dynamic clustering of SLP-76 and FcepsilonRI signaling in mast cells. Silverman, M.A., Shoag, J., Wu, J., Koretzky, G.A. Mol. Cell. Biol. (2006) [Pubmed]
  17. Role of the adapter protein SLP-76 in GPVI-dependent platelet procoagulant responses to collagen. Leo, L., Di Paola, J., Judd, B.A., Koretzky, G.A., Lentz, S.R. Blood (2002) [Pubmed]
  18. Perturbed regulation of ZAP-70 and sustained tyrosine phosphorylation of LAT and SLP-76 in c-Cbl-deficient thymocytes. Thien, C.B., Bowtell, D.D., Langdon, W.Y. J. Immunol. (1999) [Pubmed]
  19. NK cytokine secretion and cytotoxicity occur independently of the SLP-76 adaptor protein. Peterson, E.J., Clements, J.L., Ballas, Z.K., Koretzky, G.A. Eur. J. Immunol. (1999) [Pubmed]
  20. In vitro and in vivo macrophage function can occur independently of SLP-76. Myung, P.S., Clements, J.L., White, D.W., Malik, Z.A., Cowdery, J.S., Allen, L.H., Harty, J.T., Kusner, D.J., Koretzky, G.A. Int. Immunol. (2000) [Pubmed]
  21. LAT links the pre-BCR to calcium signaling. Su, Y.W., Jumaa, H. Immunity (2003) [Pubmed]
  22. The Src homology 2 domain of Vav is required for its compartmentation to the plasma membrane and activation of c-Jun NH(2)-terminal kinase 1. Arudchandran, R., Brown, M.J., Peirce, M.J., Song, J.S., Zhang, J., Siraganian, R.P., Blank, U., Rivera, J. J. Exp. Med. (2000) [Pubmed]
  23. Immune functions in mice lacking Clnk, an SLP-76-related adaptor expressed in a subset of immune cells. Utting, O., Sedgmen, B.J., Watts, T.H., Shi, X., Rottapel, R., Iulianella, A., Lohnes, D., Veillette, A. Mol. Cell. Biol. (2004) [Pubmed]
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