Cell signaling is primarily switched by reversible protein phosphorylation, a tightly regulated process controlled by the opposing actions of kinases and phosphatases. Protein tyrosine phosphatases (PTPs) are widely recognized as negative regulators, counteracting protein tyrosine kinases (PTKs) to attenuate signaling. Paradoxically, however, certain PTPs can enhance signaling in some contexts, with the underlying mechanisms remaining elusive. Recent studies have identified two PTP family members, DUSP14 and PTPN6, from Pacific white shrimp Penaeus vannamei , revealing that DUSP14 suppresses the JAK-STAT pathway by dephosphorylating STAT, while PTPN6 exerts a promotive effect. Here, the molecular mechanism of the positive regulatory role of PTPN6 in JAK-STAT signaling and its functional links with DUSP14 were explored. We showed that both PTPN6 and DUSP14 interacted with and dephosphorylated STAT, with DUSP14 exhibiting a higher activity level. Both phosphatases showed similar transcriptional trends following immune stimulation. Competition between PTPN6 and DUSP14 for STAT binding results in reduced DUSP14-mediated dephosphorylation, leading to a relative increase in STAT phosphorylation and activation. This mechanism, akin to “competitive antagonism” or “competitive inhibition,” could explain the positive regulatory effect of PTPN6 on the JAK-STAT pathway. Moreover, the role of the PTPN6/DUSP14 competitive system in antibacterial and antiviral immune responses was further investigated in vivo . Collectively, these findings establish a novel paradigm of “molecular competition” in signal transduction, offering a mechanistic explanation for the positive regulatory role of phosphatases and providing new perspectives on the regulation of signaling networks.
Luo et al. (Fri,) studied this question.