Abstract
The mitogen activated protein kinase (MAPK) signaling cascades transmit extracellular stimulations to generate various cellular responses via the sequential and reversible phosphorylation of kinases. Since the strength and duration of kinase phosphorylation within the pathway determine the cellular response, both kinases and phosphatases play an essential role in the precise control of MAPK pathway activation and attenuation. Thus, the identification of pathway-specific phosphatases is critical for understanding the functional mechanisms by which the MAPK pathway is regulated. To identify phosphatases specific to the c-Jun N-terminal kinase (JNK) MAPK pathway, a synthetic screening approach was utilized in which phosphatases were individually tethered to the JNK pathway specific-JIP1 scaffold protein. Of 77 mammalian phosphatases tested, PTPN1 led to the inhibition of JNK pathway activation. Further analyses revealed that of three pathway member kinases, PTPN1 directly dephosphorylates JNK, the terminal kinase of the pathway, and negatively regulates the JNK MAPK pathway. Specifically, PTPN1 appears to regulate the overall signaling magnitude, rather than the adaptation timing, suggesting that PTPN1 might be involved in the control and maintenance of signaling noise. Finally, the negative regulation of the JNK MAPK pathway by PTPN1 was found to reduce the tumor necrosis factor α (TNFα)-dependent cell death response.
Highlights
The mitogen-activated protein kinase (MAPK) pathways are evolutionally conserved among eukaryotes, and regulate diverse cellular responses, including cell proliferation, differentiation, and death[1,2]
Previous studies have shown that PTPN1 directly dephosphorylates insulin receptor (IR) and insulin receptor substrates (IRS), which results in downregulation of insulin signaling[36,37]
After tumor necrosis factor α (TNFα)-stimulation, changes in the level of Jun N-terminal kinase (JNK) pathway induced by a given JIP1-phosphatase fusion protein was assessed via immunoblot analysis of phosphorylated JNK
Summary
The mitogen-activated protein kinase (MAPK) pathways are evolutionally conserved among eukaryotes, and regulate diverse cellular responses, including cell proliferation, differentiation, and death[1,2]. When expressed as a JIP1-phosphatase fusion protein, some phosphatases may inactivate the JNK pathway nonspecifically via enforced close proximity, and/or interrupt JNK signal transduction via disruption of the three-dimensional structure of JIP1 signaling complex To exclude these potential false-negative effects, downregulation of JNK pathway by each analyzed phosphatase was confirmed by assessment of the co-expression of the corresponding phosphatase in its free form with JIP1. Together, this approach led to the identification of a novel phosphatase, non-transmembrane protein tyrosine phosphatase 1 (PTPN1). PTPN1 was shown to reduce TNFα-stimulated cell death responses via direct dephosphorylation of JNK, and was identified as a novel negative regulator of JNK signaling pathway
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