Activation of the Jnk signaling pathway by a dual-specificity phosphatase, JSP-1

Abstract

The mitogen-activated protein kinases (MAPKs) are integral to the mechanisms by which cells respond to physiological stimuli, such as growth factors, hormones, and cytokines, and to a wide variety of environmental stresses. The MAPKs, which are stimulated by phosphorylation of a TXY motif in their activation loop, are components of signal transduction cascades in which sequential activation of protein kinases culminates in their activation and their subsequent phosphorylation of various effector proteins that mediate the physiological response. MAPKs are also subject to dephosphorylation and inactivation, both by enzymes that recognize the residues of the TXY motif independently and by dual specificity phosphatases, which dephosphroylate both Tyr and Ser͞Thr residues. We report the identification and characterization of a novel dual specificity phosphatase. Contrary to expectation, this broadly expressed enzyme did not inactivate MAPKs in transient cotransfection assays but instead displayed the capacity to function as a selective activator of the MAPK Jnk, hence the name, Jnk Stimulatory Phosphatase-1 (JSP-1). This study illustrates a new aspect of the regulation of MAPK-dependent signal transduction and raises the possibility that JSP-1 may offer a different perspective to the study of various inflammatory and proliferative disorders associated with dysfunctional Jnk signaling.

VHY, a Novel Myristoylated Testis-restricted Dual Specificity Protein Phosphatase Related to VHX

“…VHX associates with p38 and Jnk in vivo but not in vitro (30,47), suggesting that the interaction requires additional components. Candidates include MKK7 or c-Jun, both of which interact with VHX (31,47). Together, these results indicate that VHX may play a regulatory role in the Jnk or p38 pathways, but they do not yet reveal what phosphoprotein(s) VHX dephosphorylates.…”

“…SKRP1 is involved in the regulation of Jnk and interacts with its upstream regulators MKK7 and ASK1 (apoptosis signal-regulating kinase 1) but not with MEKK1 (44,45). Finally, VHX also has been linked to MAP kinase regulation, with a proposed role as a positive regulator of Jnk activation (31,47). VHX associates with p38 and Jnk in vivo but not in vitro (30,47), suggesting that the interaction requires additional components.…”

“…This gene is now designated as DUSP22, and it has also been published by others under the names JKAP (30) and JSP1 (31). Unfortunately, the first name applied to this gene, MKPX, cannot be given priority because the name was already occupied by another gene, DUSP7 (also known as MKP-X, PYST2, and B59), only adding more confusion to the already crowded PTP nomenclature.…”

Regulation of STAT3-mediated signaling by LMW-DSP2

“…As mentioned above, we also cloned a new class of DSPs (LMW-DSP1, -DSP2, -DSP4, -DSP6, -DSP10 and -DSP11) from a mouse testis cDNA library and found that they were specifically and abundantly expressed in the testes Aoki et al, 2001). Recently, LMW-DSP2 was found to belong to the subfamily of small DSPs related to the Vaccinia virus VH1 phosphatase (Guan et al, 1991;Aoyama et al, 2001;Shen et al, 2001;Alonso et al, 2002;Chen et al, 2002). The finding that VH1 phosphatase blocked Figure 1 LIF and IL-6 induced mRNA expression of LMW-DSP2 in testicular and hepatoma cells.…”

“…LMW-DSP2 was found to dephosphorylate and deactivate p38 MAPK and JNK, but not ERK . LMW-DSP2 has also been referred to as VHX (Alonso et al, 2002), JSP1 (Shen et al, 2001) and JKAP (Chen et al, 2002). However, the physiological functions of LMW-DSPs have remained unclear, since they appear to be less efficient than many other MAPK-specific DSPs.…”