Regulation of Signal Transducer and Activator of Transcription Signaling by the Tyrosine Phosphatase PTP-BL

Abstract

Signal Transducer and Activator of Transcription (STAT) proteins are a family of latent cytoplasmic transcription factors that are activated by tyrosine phosphorylation after cytokine stimulation. One mechanism by which STAT signaling is regulated is by dephosphorylation through the action of protein tyrosine phosphatases (PTP). We have identified PTP-Basophil like (PTP-BL) as a STAT PTP. PTP-BL dephosphorylates STAT proteins in vitro and in vivo, resulting in attenuation of STAT-mediated gene activation. In CD4(+) T cells, PTP-BL deficiency leads to increased and prolonged activation of STAT4 and STAT6, and consequently enhanced T helper 1 (Th1) and Th2 cell differentiation. Taken together, our findings demonstrate that PTP-BL is a physiologically important negative regulator of the STAT signaling pathway.

JAK-STAT Signaling: From Interferons to Cytokines

“…Genetic and biochemical approaches have implicated several phosphatases in the decay of cytokine receptors and JAKs, including SHP-1, SHP-2, and potentially CD45 (2,33). Similar approaches have underscored a role for SHP-2, PTP1B, TC-PTP, and PTP-BL in STAT dephosphorylation (2,33,34). However, only two of these phosphatases, SHP-2 and TC-PTP, have been implicated in nuclear STAT dephosphorylation, which appears to be critical for STAT nuclear export (16,17,33).…”

PTPL1: a large phosphatase with a split personality

“…These PTP-BL deleted mice demonstrated increased STAT4 phosphorylation in CD4 + -T cells upon IL-12 and T-cell receptor activation [37]. The PTP-BL deleted mice also demonstrated enhanced maturation of T-cells and increased immune modulated killing following the inoculation of bacteria into their lungs [37]. These studies suggest that while PTPL1 is not critical for normal murine development, this phosphatase may participate in very different aspects of cellular physiology.…”

“…The second model created was a complete knock-out of PTP-BL. These PTP-BL deleted mice demonstrated increased STAT4 phosphorylation in CD4 + -T cells upon IL-12 and T-cell receptor activation [37]. The PTP-BL deleted mice also demonstrated enhanced maturation of T-cells and increased immune modulated killing following the inoculation of bacteria into their lungs [37].…”

“…In a similar experimental design, a substrate-trapping mutant of PTPL1 co-immunoprecipitated with HER2 in epidermal growth factor stimulated HEK293 cells that over-expressed exogenous HER2, thus making it a putative substrate [21]. STAT4 was identified as a putative substrate of PTP-BL, the mouse homolog of PTPL1 [37]. Additional work will be necessary in order to definitively prove that IκBα, IRS-1, HER2, and STAT4 are bona fide substrates of PTPL1.…”

Expression of the putative tumor suppressor gene PTPN13/PTPL1 is an independent prognostic marker for overall survival in breast cancer

“…Published studies using mutant mice that lack PTPN13 protein product or phosphatase activity did not report any effect on tumor susceptibility. Indeed none phenotypic consequences have been reported for PTPN13 KO mice 35 and studies of mice that lack PTPN13 phosphatase activity have focused on hematopoietic cell lineages and the peripheral nervous system, 36 which were previously shown to express this phosphatase. 37,38 Thus, crossbreeding of these mice with mammary tumor model mice could be used to evaluate the role of PTPL1 in tumor progression and susceptibility.…”