The Caenorhabditis elegans MAPK phosphatase VHP-1 mediates a novel JNK-like signaling pathway in stress response

Abstract

Mitogen-activated protein kinases (MAPKs) are integral to the mechanisms by which cells respond to physiological stimuli and to a wide variety of environmental stresses. MAPK cascades can be inactivated at the MAPK activation step by members of the MAPK phosphatase (MKP) family. However, the components that act in MKP-regulated pathways have not been well characterized in the context of whole organisms. Here we characterize the Caenorhabditis elegans vhp-1 gene, encoding an MKP that acts preferentially on the c-Jun N-terminal kinase (JNK) and p38 MAPKs. We found that animals defective in vhp-1 are arrested during larval development. This vhp-1 defect is suppressed by loss-of-function mutations in the kgb-1, mek-1, and mlk-1 genes encoding a JNK-like MAPK, an MKK7-type MAPKK, and an MLK-type MAPKKK, respectively. The genetic and biochemical data presented here demonstrate a critical role for VHP-1 in the KGB-1 pathway. Loss-of-function mutations in each component in the KGB-1 pathway result in hypersensitivity to heavy metals. These results suggest that VHP-1 plays a pivotal role in the integration and fine-tuning of the stress response regulated by the KGB-1 MAPK pathway.

Caenorhabditis elegans microRNAs of the let-7 family act in innate immune response circuits and confer robust developmental timing against pathogen stress

“…The role of the p38 pathway in this process is supported by our observation that loss-of-function mutations that disable the p38 MAPK pathway block the phenotypic enhancement of let-7-Fam miRNA mutants on P. aeruginosa. Also in support of this conclusion is our result that constitutive activation of p38 by knocking down of a negative regulator of p38 signaling, vhp-1 (the p38 phosphatase) (41,42), phenocopied the P. aeruginosa-induced heterochronic phenotype enhancement in let-7-Fam miRNA mutants (Fig. S2 F and G).…”

Systemic and cell intrinsic roles of Gqα signaling in the regulation of innate immunity, oxidative stress, and longevity in Caenorhabditis elegans

“…Oxidative stress and pathogen resistance are thought to be linked because insulin/IGF1 and p38 MAPK signaling mutants showed altered oxidative stress and pathogen resistance (3,7,10,12). For example, mutants in genes within IIS, such as daf-2, age-1, and akt-1 are resistant to pathogens and oxidative stress.…”

“…Oxidative stress response is also regulated by the p38 MAPK cascade, which in C. elegans comprises of a three-tiered kinase cascade leading to phosphorylation by a MAPK kinase homolog SEK-1 and activation of the p38 MAPK homolog PMK-1 (6). Loss of either sek-1 or pmk-1 function results in increased sensitivity to oxidative stress (7). The p38 MAPK pathway affects oxidative stress resistance cell autonomously in part through regulation of the Nrf family transcription factor SKN-1 in the intestine (8,9).…”

PAK Is Regulated by PI3K, PIX, CDC42, and PP2Cα and Mediates Focal Adhesion Turnover in the Hyperosmotic Stress-induced p38 Pathway

“…On the other hand, the MAPK dual-specificity phosphatases have also been shown to be important regulators of MAPK signaling. In HeLa cells, MKP1 has been shown to mediate anti-inflammation through inhibition of p38 (46) and in Caenorhabditis elegans, a MKP7 ortholog VHP1 is reported to down-regulate KGB1, an ortholog of mammalian Jnk1 and is involved in heavy metal sensitivity (47). The MAPK dual-specificity phosphatases may also have roles in regulating MAPK pathways in hyperosmotic response, perhaps after the acute phase of osmotic stress.…”