The Dual Specificity JKAP Specifically Activates the c-Jun N-terminal Kinase Pathway

Abstract

MAPKs are activated by a wide range of diverse stimuli and are essential for various cellular processes, such as stress responses, apoptosis, proliferation, differentiation, and early embryonic development (1-3). The prototypical MAPK signaling cascade is a three-kinase module, consisting of MAP kinase kinase kinase (MAP3K), MAP kinase kinase (MAP2K), and MAPK (1, 2, 4). The upstream molecules that link the MAPK module to extracellular stimuli include small G proteins and a group of mammalian Ste20-like kinases, including hematopoietic progenitor kinase 1 (HPK1), germinal center kinase (GCK), HKP1/germinal center kinase-like kinase, germinal center kinase-like kinase (GLK), and kinase homologous to Ste20 (KHS), which have been characterized as potential MAP kinase kinase kinase kinases (MAP4Ks) for the JNK pathway (1, 2, 4, 5). Within the three-kinase module, MAPKs are phosphorylated on both threonine and tyrosine residues within their signature sequence TXY motif by a dual specificity protein kinase MAP2K. These motifs include TEY in ERK, TPY in JNK, and TGY in p38. MAP2K are activated by phosphorylation of serine/threonine residues by MAP3Ks (1, 2, 4). In the case of ERK1/2, phosphorylation of the TEY motif also contributes to the dimerization and nuclear translocation of ERK1/2 in addition to mediating its activation (6). The extracellular stimuli-induced activation of MAPKs is transient under many conditions, and it has been well established that protein phosphatases play an essential role in the down-regulation of MAP kinases. A variety of classes of protein phosphatases, including tyrosine-specific protein phosphatases, serine/threonine protein phosphatases, and a family of dual specificity protein phosphatases (DSPs), have been implicated in the negative regulation of MAPKs (7-9). Among them, DSPs are the major group of phosphatases that contribute to the regulated inactivation of MAP kinases by dephosphorylating both phosphotyrosine and phosphothreonine residues within the TXY motif, thus also called MAP kinase phosphatases (MKPs) (7-9). Most MKPs identified so far consist of a conserved catalytic region and an extended regulatory region. However, some MKPs lack this regulatory region, such as VH1 (10) and VH1-related (VHR) phosphatase (11). The regulatory

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.…”

“…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. Candidates include MKK7 or c-Jun, both of which interact with VHX (31,47).…”

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.…”