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• 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]