Deficiency in Expression of the Signaling Protein Sin/Efs Leads to T-Lymphocyte Activation and Mucosal Inflammation

Abstract

Our studies have concentrated on elucidating the role of the signaling protein Sin in T-lymphocyte function. We have previously shown that Sin overexpression inhibits T-lymphocyte development and activation. Here we show that Sin-deficient mice exhibit exaggerated immune responses characterized by enhanced cytokine secretion and T-cell-dependent antibody production. Excessive T-cell responses in young mice correlate with spontaneous development of inflammatory lesions in different organs of aged Sin ؊/؊ mice, particularly the small intestine. The intestinal inflammation is characterized by T-and B-cell infiltrates in the lamina propria, which correlate with crypt enlargement and marked villus expansion and/or damage. Similar to the human intestinal inflammatory disorder Crohn's disease (CD), and in contrast to most mouse models of mucosal inflammation, inflammatory lesions in the gastrointestinal tract of Sin ؊/؊ mice are restricted to the small bowel. Taken together, these results suggest that Sin regulates immune system and T-lymphocyte function and that immune system dysfunction in the absence of Sin may underlie the pathogenesis of tissue-specific inflammation and enteropathies such as CD.

Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin

“…S2 B). These results, together with the expression pattern of Sin and data showing no discernible differences in the intrinsic signaling properties of Sin / CD3 + T cells as compared with controls (assayed by proliferation in response to TCR activation [Donlin et al, 2005], total phosphotyrosine levels, PLC- phosphorylation, MAP-kinase activation, and intracellular calcium release [unpublished data]), strongly suggest that the absence of Sin from the thymic stroma and not the hematopoietic compartment contributes to autoimmunity in Sin / mice.…”

Decreased expression of EFS is correlated with the advanced prostate cancer

“…Indeed, we have seen that high EFS level repressed cell proliferation, migration, and colony formation abilities of all the investigated PCa cells. Donlin et al reported that EFS is an important regulator in T lymphocyte development and that EFS deficiency leads to aberrant T cell activation and, consequently, inflammation [31,32]. It is known that the inflammation contributes to cancer development and progression [33].…”

Molecular basis for HEF1/NEDD9/Cas-L action as a multifunctional co-ordinator of invasion, apoptosis and cell cycle

“…Relatively little is known about Efs/Sin, although recent reports suggest important activities in lymphoid cells [11,12]. However, in all the following discussions of HEF1/ NEDD9/Cas-L, an important consideration is the historical relationship between HEF1/NEDD9/Cas-L and its family member p130Cas.…”