TULA-Family Regulators of Platelet Activation

Abstract

The two members of the UBASH3/TULA/STS-protein family have been shown to critically regulate cellular processes in multiple biological systems. The regulatory function of TULA-2 (also known as UBASH3B or STS-1) in platelets is one of the best examples of the involvement of UBASH3/TULA/STS proteins in cellular regulation. TULA-2 negatively regulates platelet signaling mediated by ITAM- and hemITAM-containing membrane receptors that are dependent on the protein tyrosine kinase Syk, which currently represents the best-known dephosphorylation target of TULA-2. The biological responses of platelets to collagen and other physiological agonists are significantly downregulated as a result. The protein structure, enzymatic activity and regulatory functions of UBASH3/TULA/STS proteins in the context of platelet responses and their regulation are discussed in this review.

Multi-phased Kinetics and Interaction of Protein Kinase Signaling in Glycoprotein VI-Induced Platelet αIIbβ3 Integrin Activation and Degranulation

“…The revealed transient, reversible nature of convulxin-induced Y/S/T-phosphorylation indicates a powerful role of both Y-and /S/T-protein phosphatases in human platelets. [40][41][42] For instance, the prominent tyrosine phosphatase TULA-2 dephosphorylates Y-phosphorylated Syk and antagonizes GPVI-signaling, 43 whereas the ST protein phosphatase PP2A dephosphorylates Syk pS297 and components of MAPK signaling. 27,42 Interestingly, platelet tyrosine phosphorylation induced by GPVI and CLEC-2 activation was sustained for 50 minutes, when aggregation was prevented by eptifibatide, 18 suggesting that dephosphorylation can also be controlled.…”

The Ubiquitin-Associated and SH3 Domain-Containing Proteins (UBASH3) Family in Mammalian Development and Immune Response

“…Although UBASH3A and B share some structural domains, they have different functions and expression patterns [3]. The UBA domain has been shown to bind to monoubiquitin and ubiquitylated proteins, including UBASH3 family proteins when ubiquitylated [7,12]. The SH3 domain of UBASH3 family proteins mediates binding to other proteins, for example, by interacting with CBL (E3 ubiquitin ligase) [10,13].…”

TULA Proteins in Men, Mice, Hens, and Lice: Welcome to the Family

“…Importantly, changes in TULA-2 level caused by KO or microRNA-dependent modulation resulted in significant in vivo effects, such as a decrease in tail bleeding time and an increase in thrombotic reactions in model systems [16,50,51]. As a result of these studies, TULA-2 is considered one of the major negative regulators of platelet signaling and activation, as reviewed in detail in [53].…”

“…In immune cells and platelets, where the role of the TULA family has been examined extensively, the molecular basis of the observed effects is thought to be related to the ITAM-/hemITAM-mediated signaling dependent on ZAP-70 and Syk PTKs, which form a two-member Syk family (reviewed in [32,53,57,58]). Together, these studies point at the dephosphorylation of Syk-family PTKs as a major molecular mechanism in the biological functions of TULA proteins in T cells and platelets.…”

“…Another key regulatory function of the TULA family in vertebrates has been demonstrated in platelets, whose major role is to constantly survey the integrity of the blood circulatory system and to mediate hemostatic responses by forming an aggregate, which seals off a damaged area in a blood vessel [16,35,49] (reviewed in [53]). Therefore, these anucleate cells, together with nucleated thrombocytes, which are present in vertebrates other than mammals, play a role unique for vertebrates, since no invertebrate possesses a classically defined closed circulatory system [114].…”