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Gene Review

Sh2b3  -  SH2B adaptor protein 3

Mus musculus

Synonyms: AI429800, Lnk, Lymphocyte adapter protein, Lymphocyte-specific adapter protein Lnk, SH2B adapter protein 3, ...
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Disease relevance of Sh2b3

  • The in vitro proliferative capacity and absolute numbers of hematopoietic progenitors from Lnk(-/-) mice are greatly increased, in part due to hypersensitivity to several cytokines [1].
  • Lnk(-/-) mice are viable, but display marked changes in the hematopoietic compartment, including splenomegaly and abnormal lymphoid and myeloid homeostasis [1].

High impact information on Sh2b3

  • Hence, Lnk ordinarily acts to regulate B cell production [2].
  • Lnk is an SH2 domain-containing adaptor protein expressed preferentially in lymphocytes [2].
  • Further characterization of lnk(-/-) mice also revealed that full-length Lnk is a 68 kDa protein containing a conserved proline-rich region and a PH domain [2].
  • Here, we show that Lnk overexpression negatively regulates Tpo-mediated cell proliferation and endomitosis in hematopoietic cell lines and primary hematopoietic cells [3].
  • Furthermore, the Src homology 2 domain of Lnk is essential for Lnk's inhibitory function [3].

Biological context of Sh2b3


Anatomical context of Sh2b3

  • Consistent with this result, we found that in both BM and spleen, Lnk-deficient mice exhibited increased numbers of megakaryocytes with increased ploidy compared with wild-type mice [3].
  • These observations indicate that Lnk plays critical roles in the expansion and function of early hematopoietic progenitors, and provide useful clues for the amplification of hematopoietic progenitor cells [5].
  • Furthermore, Lnk inactivation causes abnormal modulation of IL-3 and stem cell factor-mediated signaling pathways [1].
  • Here we show that Lnk is also expressed in hematopoietic progenitors in bone marrow, and that in the absence of Lnk, the number and the hematopoietic ability of progenitors are significantly increased [5].
  • Lnk was predominantly expressed in the endothelial cells lining the dorsal aorta at embryonic day 11.5 (E11.5) [6].

Enzymatic interactions of Sh2b3

  • Biochemical experiments revealed that Lnk directly binds to phosphorylated tyrosine residues in JAK2 following TPO stimulation [7].

Regulatory relationships of Sh2b3

  • Consistent with these results, we also show that Lnk is highly expressed in multipotent cells and committed precursors in the erythroid, megakaryocyte, and myeloid lineages [1].
  • Single-cell transplantation of each of the paired daughter cells indicated that a combination of stem cell factor and TPO efficiently induces symmetrical self-renewal division in Lnk-deficient HSCs but not in WT HSCs [8].

Other interactions of Sh2b3

  • In addition, Lnk deficiency resulted in enhanced Epo-induced signaling pathways in splenic erythroid progenitors [4].
  • Thus, Lnk negatively modulates mpl signaling pathways and is important for Tpo-mediated megakaryocytopoiesis in vivo [3].
  • Previous studies suggested that Lnk, a 38-kDa protein consisting of a single SH2 domain and a region containing potential tyrosine phosphorylation sites, might serve to join Grb2, phospholipase C-gamma1, and phosphatidylinositol 3-kinase to the TCR [9].
  • Defective thymocyte maturation by transgenic expression of a truncated form of the T lymphocyte adapter molecule and Fyn substrate, Sin [10].
  • The adaptor protein Lnk, and the closely related proteins APS and SH2B, form a subfamily of SH2 domain-containing proteins implicated in growth factor, cytokine, and immunoreceptor signaling [1].


  1. Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice. Velazquez, L., Cheng, A.M., Fleming, H.E., Furlonger, C., Vesely, S., Bernstein, A., Paige, C.J., Pawson, T. J. Exp. Med. (2002) [Pubmed]
  2. Control of B cell production by the adaptor protein lnk. Definition Of a conserved family of signal-modulating proteins. Takaki, S., Sauer, K., Iritani, B.M., Chien, S., Ebihara, Y., Tsuji, K., Takatsu, K., Perlmutter, R.M. Immunity (2000) [Pubmed]
  3. Lnk inhibits Tpo-mpl signaling and Tpo-mediated megakaryocytopoiesis. Tong, W., Lodish, H.F. J. Exp. Med. (2004) [Pubmed]
  4. Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways. Tong, W., Zhang, J., Lodish, H.F. Blood (2005) [Pubmed]
  5. Enhanced hematopoiesis by hematopoietic progenitor cells lacking intracellular adaptor protein, Lnk. Takaki, S., Morita, H., Tezuka, Y., Takatsu, K. J. Exp. Med. (2002) [Pubmed]
  6. Regulation of hematopoietic development in the aorta-gonad-mesonephros region mediated by Lnk adaptor protein. Nobuhisa, I., Takizawa, M., Takaki, S., Inoue, H., Okita, K., Ueno, M., Takatsu, K., Taga, T. Mol. Cell. Biol. (2003) [Pubmed]
  7. Lnk controls mouse hematopoietic stem cell self-renewal and quiescence through direct interactions with JAK2. Bersenev, A., Wu, C., Balcerek, J., Tong, W. J. Clin. Invest. (2008) [Pubmed]
  8. Lnk negatively regulates self-renewal of hematopoietic stem cells by modifying thrombopoietin-mediated signal transduction. Seita, J., Ema, H., Ooehara, J., Yamazaki, S., Tadokoro, Y., Yamasaki, A., Eto, K., Takaki, S., Takatsu, K., Nakauchi, H. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  9. Characterization of Lnk. An adaptor protein expressed in lymphocytes. Takaki, S., Watts, J.D., Forbush, K.A., Nguyen, N.T., Hayashi, J., Alberola-Ila, J., Aebersold, R., Perlmutter, R.M. J. Biol. Chem. (1997) [Pubmed]
  10. Defective thymocyte maturation by transgenic expression of a truncated form of the T lymphocyte adapter molecule and Fyn substrate, Sin. Donlin, L.T., Roman, C.A., Adlam, M., Regelmann, A.G., Alexandropoulos, K. J. Immunol. (2002) [Pubmed]
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