Impaired Lymphopoiesis and Altered B Cell Subpopulations in Mice Overexpressing Lnk Adaptor Protein

Abstract

Lnk is an adaptor protein expressed primarily in lymphocytes and hemopoietic precursor cells. Marked expansion of B lineage cells occurs in lnk−/− mice, indicating that Lnk regulates B cell production by negatively controlling pro-B cell expansion. In addition, lnk−/− hemopoietic precursors have an advantage in repopulating the hemopoietic system of irradiated host animals. In this study, we show that Lnk overexpression results in impaired expansion of lymphoid precursor cells and altered mature B cell subpopulations. The representation of both B lineage and T lineage cells was reduced in transgenic mice overexpressing Lnk under the control of a lymphocyte-specific expression vector. Whereas the overall number of B and T cells was correlated with Lnk protein expression levels, marginal zone B cells in spleen and B1 cells in the peritoneal cavity were relatively resistant to Lnk overexpression. The C-terminal tyrosine residue, conserved among Lnk family adaptor proteins, was dispensable for the negative regulatory roles of Lnk in lymphocyte development. Our results illuminate the novel negative regulatory mechanism mediated by the Lnk adaptor protein in controlling lymphocyte production and function.

Increased Insulin Sensitivity and Hypoinsulinemia in APS Knockout Mice

“…These observations present a reasonable synonym with the negative regulation by Lnk in c-Kit signals (14,37). In contrast, positive regulatory roles for SH2-B have been demonstrated in SH2-B Ϫ/Ϫ mice (13).…”

“…Increased plasma levels of leptin and adiponectin in APS ؊/؊ mice. Leptin and adiponectin, both major adipocyte secretory proteins, are thought to play important roles in glucose homeostasis and insulin resistance (37)(38)(39)(40). Plasma concentrations of leptin and adiponectin in APS Ϫ/Ϫ mice were significantly higher than concentrations in APS ϩ/ϩ mice ( Fig.…”

The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis

“…SH4B3 overproduction in lymphoid precursors resulted in a reduction in the number of both B and T cells, whereas the lack of the SH4B3 gene showed enhanced B-cell production. 29 The association of rs1678542/KIF5A variant with MS, uncovered for the first time in this work, was first associated with RA in European populations. 18,30 The rs1678542/KIF5A is located 194 kb apart from the rs703842/methyltransferase-like protein 1 3 0 UTR with a linkage disequilibrium r 2 of 0.184.…”

Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways

“…Therefore, Lnk may negatively regulate signaling pathways originating from multiple cytokine receptors through a similar mechanism. Interestingly, the conserved tyrosine near the C-terminus of Lnk, Y536, is dispensable for the negative regulatory roles of Lnk in lymphocyte development 25 and Tpo-mediated megakaryocytopoiesis. 11 In contrast, we found that Y536 is important, but not required, for modulating Epo-dependent 32D cell proliferation or erythroblast survival.…”