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STS-1 and STS-2 form a small family of proteins that are involved in the regulation of signal transduction by protein–tyrosine kinases. Both proteins are composed of a UBA domain, an esterase domain, an SH3 domain, and a PGM domain. They use their UBA and SH3 domains to modify or rearrange protein–protein interactions and their PGM domain to catalyze protein–tyrosine dephosphorylation. In this manuscript, we discuss the various proteins that have been found to interact with STS-1 or STS-2 and describe the experiments used to uncover their interactions. [ABSTRACT FROM AUTHOR]

The two members of the UBASH3/STS/TULA protein family have been shown to critically regulate key biological functions, including immunity and hemostasis, in mammalian biological systems. Negative regulation of signaling through immune receptor tyrosine-based activation motif (ITAM)- and hemITAM-bearing receptors mediated by Syk-family protein tyrosine kinases appears to be a major molecular mechanism of the down-regulatory effect of TULA-family proteins, which possess protein tyrosine phosphatase (PTP) activity. However, these proteins are likely to carry out some PTP-independent functions as well. Whereas the effects of TULA-family proteins overlap, their characteristics and their individual contributions to cellular regulation also demonstrate clearly distinct features. Protein structure, enzymatic activity, molecular mechanisms of regulation, and biological functions of TULA-family proteins are discussed in this review. In particular, the usefulness of the comparative analysis of TULA proteins in various metazoan taxa, for identifying potential roles of TULA-family proteins outside of their functions already established in mammalian systems, is examined. [ABSTRACT FROM AUTHOR]

The suppressor of TCR signaling (Sts) proteins, Sts-1 and Sts-2, are a pair of closely related signaling molecules that belong to the histidine phosphatase (HP) family of enzymes by virtue of an evolutionarily conserved C-terminal phosphatase domain. HPs derive their name from a conserved histidine that is important for catalytic activity and the current evidence indicates that the Sts HP domain plays a critical functional role. Sts-1HP has been shown to possess a readily measurable protein tyrosine phosphatase activity that regulates a number of important tyrosine-kinase-mediated signaling pathways. The in vitro catalytic activity of Sts-2HP is significantly lower than that of Sts-1HP, and its signaling role is less characterized. The highly conserved unique structure of the Sts proteins, in which additional domains, including one that exhibits a novel phosphodiesterase activity, are juxtaposed together with the phosphatase domain, suggesting that Sts-1 and -2 occupy a specialized intracellular signaling niche. To date, the analysis of Sts function has centered predominately around the role of Sts-1 and -2 in regulating host immunity and other responses associated with cells of hematopoietic origin. This includes their negative regulatory role in T cells, platelets, mast cells and other cell types, as well as their less defined roles in regulating host responses to microbial infection. Regarding the latter, the use of a mouse model lacking Sts expression has been used to demonstrate that Sts contributes non-redundantly to the regulation of host immunity toward a fungal pathogen (C. albicans) and a Gram-negative bacterial pathogen (F. tularensis). In particular, Sts-/- animals demonstrate significant resistance to lethal infections of both pathogens, a phenotype that is correlated with some heightened anti-microbial responses of phagocytes derived from mutant mice. Altogether, the past several years have seen steady progress in our understanding of Sts biology. [ABSTRACT FROM AUTHOR]

Sts-1 is a multidomain protein that plays an important role in T-cell signaling. Sts-1 contains a ubiquitin-association (UBA) domain at the N-terminus, followed by an Src homology-3 (SH3) domain and a C-terminal domain that shares sequence homology to phosphoglycerate mutases (PGMs). The C-­terminal domain of Sts-1, Sts-1PGM, crystallizes in space group C2 with two different crystal forms. The first crystal form contains two or three Sts-1PGM molecules in the asymmetric unit and diffracts to 1.82 Å resolution, with unit-cell parameters a = 116.2, b = 74.3, c = 100.1 Å, α = γ = 90, β = 101.5°. The second crystal form contains four or six Sts-1PGM molecules in the asymmetric unit, with unit-cell parameters a = 214.9, b = 75.1, c = 116.4 Å, α = γ = 90, β = 111.6°. Greater than 95% complete native and SeMet data sets have been collected and structure determination using the multiple anomalous dispersion (MAD) technique is ongoing. [ABSTRACT FROM AUTHOR]

• UBASH3/STS/TULA-family proteins consist of the UBA, SH3 and phosphatase domains. • The two family members markedly differ in tissue expression and phosphatase activity. • Regulatory effects of these proteins mostly depend on their phosphatase activity. • TULA proteins regulate signaling in various systems, including T cells and platelets. • Down-regulation of Syk-mediated signaling is to-date the best-studied effect of TULA-2. Two members of the UBASH3/STS/TULA family exhibit a unique protein domain structure, which includes a histidine phosphatase domain, and play a key role in regulating cellular signaling. UBASH3A/STS-2/TULA is mostly a lymphoid protein, while UBASH3B/STS-1/TULA-2 is expressed ubiquitously. Dephosphorylation of tyrosine-phosphorylated proteins by TULA-2 and, probably to a lesser extent, by TULA critically contribute to the molecular basis of their regulatory effect. The notable differences between the effects of the two family members on cellular signaling and activation are likely to be linked to the difference between their specific enzymatic activities. However, these differences might also be related to the functions of their domains other than the phosphatase domain and independent of their phosphatase activity. The down-regulation of the Syk/Zap-70-mediated signaling, which to-date appears to be the best-studied regulatory effect of TULA family, is discussed in detail in this publication. [ABSTRACT FROM AUTHOR]