Multidomain STS/TULA proteins are novel cellular regulators

Abstract

SummaryProteins of the STS/TULA family recently emerged as important regulators of cellular functions. They exhibit a unique domain architecture, featuring at least three interactive/functional domains. Despite a significant degree of homology between the two members of this family, there are considerable functional differences between them. Thus, one of them is ubiquitously expressed in mammalian tissues and exhibits high phosphatase activity, whereas the other one is expressed in lymphocytes only and exhibits very low phosphatase activity, but is capable of promoting apoptosis, an activity unique for this family member. Among several functions reported for STS/TULA proteins, the most characterized one is the regulation of protein tyrosine kinase-mediated signaling. Interestingly, gene deletion of neither family member results in a discernible phenotype, whereas simultaneous deletion of both members causes hyperreactivity of T cells. Despite their apparent importance, the physiological role and the molecular basis of the effects of STS/ TULA proteins remain poorly understood. This brief review summarizes what is currently known about the STS/TULA family and outlines the unresolved questions in this area.2008 IUBMB IUBMB Life, 60(4): [224][225][226][227][228][229][230][231] 2008

A Human Type 1 Diabetes Susceptibility Locus Maps to Chromosome 21q22.3

“…Further impetus for follow-up study of this SNP came from its location within the sixth intron of the gene UBASH3A, which is expressed predominantly in T-cells and is involved in the regulation of signaling from the antigen receptor (25). The putative disease-associated allele was relatively common, with a minor allele frequency of 0.45 in unaffected founders.…”

“…UBASH3A is expressed predominantly in T-cells, where it interacts with c-CBL through its SH3 domain and binds to ubiquitin and ubiquitylated proteins via its ubiquitinassociated domain ( (25). In T-cells, it acts in part by inhibiting c-CBL-mediated downregulation of protein tyrosine kinases such as ZAP70 that are activated upon T-cell receptor stimulation (32).…”

Determination of the Substrate Specificity of Protein-tyrosine Phosphatase TULA-2 and Identification of Syk as a TULA-2 Substrate

“…However, phosphorylation of this site is largely constitutive under conditions of our experiments and, thus, may be regulated quite differently from the other sites studied. Another possible reason for the observed discrepancies might be the contribution of the N-terminal ubiquitin-association and Src homology 3 domains, which mediate protein-protein interactions (4,5,7,11,12,(33)(34)(35)(36). These protein binding domains may target the catalytic domain of TULA-2 to specific protein substrates (e.g.…”

Lack of association between polymorphisms in the UBASH3A gene and autoimmune thyroid disease: a case control study

“…Both of them are suppressors of TCR signaling and can regulate TCR signaling pathways negatively. The two proteins exhibit a unique architecture comprised of three conserved and functional domain: an N-terminal ubiquitin associated (UBA) domain that can bind mono-and poly-ubiquitin, a central Src homology 3 (SH3) domain which can participate in protein-protein interactions, and a C-terminal PGM (phosphoglycerate mutase) acting as phosphatases or phosphotransferases (14,22). Unlike the other protein, TULA/STS-2/UBASH3A is only expressed within lymphocytes and has a low phosphatase activity but a unique ability of promoting T-cell apoptosis (23,24).…”

“…UBASH3A is a potent regulator of cellular functions and is expressed predominantly in T-cells, having a suppressing effect on TCR signaling and activation (14). Lack of TULA proteins resulted in hyper-reactivity of T cells (15).…”