Regulation of the p38-MAPK pathway by hyperosmolarity and by WNK kinases.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
25 08 2022
25 08 2022
Historique:
received:
18
04
2022
accepted:
16
08
2022
entrez:
25
8
2022
pubmed:
26
8
2022
medline:
30
8
2022
Statut:
epublish
Résumé
p38-MAPK is a stress-response kinase activated by hyperosmolarity. Here we interrogated the pathways involved. We show that p38-MAPK signaling is activated by hyperosmotic stimulation in various solutions, cell types and colonic organoids. Hyperosmolarity sensing is detected at the level of the upstream activators of p38-MAPK: TRAF2/ASK1 (but not Rac1) and MKK3/6/4. While WNK kinases are known osmo-sensors, we found, unexpectedly, that short (2 h) inhibition of WNKs (with WNK463) led to elevated p38-MAPK activity under hyperosmolarity, which was mediated by WNK463-dependent stimulation of TAK1 or TRAF2/ASK1, the upstream activators of MKK3/6/4. However, this effect was temporary and was reversed by long-term (2 days) incubation with WNK463. Accordingly, 2 days (but not 2 h) inhibition of p38-MAPK or its upstream activators ASK1 or TAK1, or WNKs, diminished regulatory volume increase (RVI) following cell shrinkage under hyperosmolarity. We also show that RVI mediated by the ion transporter NKCC1 is dependent on p38-MAPK. Since WNKs are known activators of NKCC1, we propose a WNK- > NKCC1- > p38-MAPK pathway that controls RVI. This pathway is augmented by NHE1. Additionally, hyperosmolarity inhibited mTORC1 activation and cell proliferation. Thus, activation of p38-MAPK and WNKs is important for RVI and for cell proliferation.
Identifiants
pubmed: 36008477
doi: 10.1038/s41598-022-18630-w
pii: 10.1038/s41598-022-18630-w
pmc: PMC9411163
doi:
Substances chimiques
TNF Receptor-Associated Factor 2
0
p38 Mitogen-Activated Protein Kinases
EC 2.7.11.24
MAP Kinase Kinase 3
EC 2.7.12.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
14480Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK098145
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK119252
Pays : United States
Organisme : CIHR
ID : FDN-159918
Pays : Canada
Informations de copyright
© 2022. The Author(s).
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