Phosphatase Subfamily STS

Phosphatase Classification: Fold HP: Superfamily HP (histidine phosphatase): HP, branch1 family: Subfamily STS

STS is protein tyrosine phosphatase involved in T-cell receptor signaling. In particular, STS dephosphorylates kinases Syk and ZAP-70 of Syk subfamily. STS is conserved in metazoan.

Evolution

STS subfamily is found in most metazoan. Human has two STSs: STS-1 (TULA-2 or UBASH3B) and STS-2 (TULA-1 or UBASH3A). STS-2 is present in lobe-finned fish, birds and mammals, but not other bony fishes. STS-1 emerged earlier than STS-2, which is found in most metazoan, from sponge to insects, fishes, birds, and mammals. C. elegans has five STS genes, but all of them lack UBA (ubiquitin-associated domain), 2H phosphoesterase, and SH3 domains. Interestingly, STS substrates, Syk and ZAP-70, both of which belong to SYK kinase family, is absent from C. elegans.

Domain

Typical STS consists of four domains: UBA (ubiquitin-associated domain), 2H phosphoesterase [1], SH3 and HP2 phosphatase domain. The UBA, 2H and SH3 domains are absent from C. elegans STSs.

Functions

Human STS-1 and STS-2 are involved in T Cell Receptor (TCR) signaling pathways by regulating kinase Syk and ZAP-70, two members of Syk kinase subfamily. STS-2 is predominantly in naive and mature T cells , whereas STS-1 is expressed ubiquitously.

STS-1 decreases tyrosine phosphorylation of Syk in vivo and in vitro [2, 3]. Inactivated STS-1 increases tyrosine phosphorylation of Syk in cells co-transfected to overexpress these proteins, thus acting as a dominant-negative form that suppresses dephosphorylation of Syk caused by endogenous STS-1. However, the same assay on STS-2 shows the phosphatase activity of STS-2 is negligible compared to STS-1. The UBA domain of STS-2 and SH3-dependent Cbl-binding are required for this function [4]. In addition, both STS-1 and STS-2 regulates kinase ZAP-70 activation [3].

Human STS-1 can also dephosphorylate phospho-tyrosines on EGFR. The histidine phosphatase domain of STS-1, but not of STS-2, dephosphorylates the EGFR at multiple tyrosines, and thereby terminating its signalling and endocytosis [5].

References

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