Protein tyrosine phosphatases as wardens of STAT signaling

Abstract

Signaling by signal transducers and activators of transcription (STATs) is controlled at many levels of the signaling cascade. Protein tyrosine phosphatases (PTPs) regulate STAT activation at several layers, including direct pSTAT dephosphorylation in both cytoplasm and nucleus. Despite the importance of this regulation mode, many aspects are still incompletely understood, e.g., the identity of PTPs acting on certain members of the STAT family. After a brief introduction into the STAT and PTP families, we discuss here the current knowledge on PTP mediated regulation of STAT activity, focusing on the interaction of individual STATs with specific PTPs. Finally, we highlight open questions and propose important tasks of future research.

Keywords: PTP; STAT; dephosphorylation; protein tyrosine phosphatase; signal transducer and activator of transcription.

Figure 1. JAK-STAT signaling is regulated by protein tyrosine phosphatases at several levels. Activation of cell surface receptors leads to activation of associated Janus- or TYK2-kinases (designated JAK), and in turn tyrosine phosphorylation of the receptors, and recruitment and tyrosine phosphorylation of STAT molecules. Different protein tyrosine phosphatases, such as the transmembrane PTPs CD45 and PTPε, as well as the cytoplasmic PTPs PTP1B, TCPTP, and SHP-1 can attenuate JAK activation by dephosphorylation. SHP-1 (and the related PTP SHP-2) can associate through their SH2 domains with phosphorylated cytokine receptors, and can modulate JAK activation, and also further signaling pathways initiated by ligand stimulation (not shown). Tyrosine phosphorylated STATs (denoted pSTAT) form dimers, which are capable of translocation to the nucleus, by reciprocal interaction of the (C-terminally located) SH2-domains with the phosphotyrosine motifs. Dephosphorylation of pSTATs by PTPs occurs in the cytoplasm and nucleus, leading to control of amplitude and duration of STAT signaling. Dephosphorylated STAT molecules become available for a new cycle of activation.

Figure 2. Regulation of STAT signaling by T-cell protein tyrosine phosphatase (TCPTP). pSTAT dimers can be transported into the nucleus, bind to DNA and regulate gene transcription. In the pSTAT dimers formed by reciprocal interaction of the SH2-domains with the phosphotyrosines (so-called “parallel” dimers), the phosphotyrosines are buried. STAT molecules can also form “antiparallel” dimers through their N-terminal domains, which exist in equilibrium with the parallel dimers. In the antiparallel state, protein tyrosine phosphatases (PTPs) can more easily access the pSTAT phosphotyrosine residues. A major STAT PTP is TCPTP45, which can shuttle between cytoplasm and nucleus and dephosphorylate both, nuclear and cytoplasmic pSTAT1, 3, and 6, and possibly further STATs.