TULA-family Proteins: a New Class of Cellular Regulators

Proteins of the UBASH3/STS/TULA family recently emerged as potent regulators of cellular functions. They are characterized by a unique architecture, featuring at least three functional domains. One of them is a histidine phosphatase domain, which mediates the protein tyrosine phosphatase activity of these proteins. Recent studies demonstrated that UBASH3/STS/TULA-family proteins play a key role in down-regulating receptor-mediated signal transduction and physiologic responses of T cells and platelets in vitro and in vivo. The Syk-family protein tyrosine kinases Syk and Zap-70 were identified as major targets of TULA-2 in full agreement with the suppressive effect of this phosphatase in systems where Syk and Zap-70 carry out the essential early steps of signal transduction. In spite of significant similarity between TULA and TULA-2, there are also considerable functional differences between them. Thus, TULA-2 is expressed ubiquitously in mammalian tissues and exhibits high phosphatase activity, whereas TULA is expressed specifically in lymphocytes and exhibits low phosphatase activity. However, TULA also functions as a down-regulator of cellular responses, and therefore its role may be mediated by dephosphorylation of yet-unknown substrates or by promoting T-cell apoptosis (the latter activity is unique for this UBASH3/STS/TULA family member). The down-regulatory role of TULA and TULA-2 revealed in experimental systems is consistent with the recently discovered association of several autoimmune diseases with certain risk alleles encoding for these proteins. .