Sh2b3/Lnk family adaptor proteins in the regulation of lymphohematopoiesis

Abstract

Sh2b3/Lnk consisting of an N-terminal proline-rich region, PH-, SH2-domains and a tyrosine phosphorylation site, forms an intracellular adaptor protein family conserved from drosophila to mammals, together with Sh2b1/SH2-B and Sh2b2/APS (adaptor protein with PH and SH2 domains). Lnk negatively regulates lymphopoiesis and early hematopoiesis. The lnk-deficiency results in enhanced production of B cells, and expansion as well as enhanced function of hematopoietic stem cells (HSCs), demonstrating negative regulatory functions of Sh2b3/Lnk in cytokine signaling. Our recent studies also revealed that Sh2b3/Lnk functions in responses controlled by cell adhesion and in crosstalk between integrin- and cytokine-mediated signaling. Importantly, recent genome-wide association studies of the autoimmune type 1 diabetes or celiac disease identified risk variants in the SH2B3/LNK region, indicating possible unrevealed functions mediated by this adaptor molecule. This review summarizes roles of Sh2b3/Lnk in the regulation of B-lymphopoiesis and HSCs expansion and function, and briefly introduces our approach for modulating HSCs function by targeting Sh2b3/Lnk-mediated pathways. © 2008, The Japan Society for Clinical Immunology. All rights reserved.