Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock.
Sensing the osmolarity of the environment is a critical response for all organisms. Whereas bacteria will migrate away from high osmotic conditions, most eukaryotic cells are not motile and use adaptive metabolic responses for survival. The p38 MAPK pathway is a crucial mediator of survival during cellular stress. We have discovered a novel scaffold protein that binds to actin, the GTPase Rac, and the upstream kinases MEKK3 and MKK3 in the p38 MAPK phospho-relay module. RNA interference (RNAi) demonstrates that MEKK3 and the scaffold protein are required for p38 activation in response to sorbitol-induced hyperosmolarity. FRET identifies a cytoplasmic complex of the MEKK3 scaffold protein that is recruited to dynamic actin structures in response to sorbitol treatment. Through its ability to bind actin, relocalize to Rac-containing membrane ruffles and its obligate requirement for p38 activation in response to sorbitol, we have termed this protein osmosensing scaffold for MEKK3 (OSM). The Rac-OSM-MEKK3-MKK3 complex is the mammalian counterpart of the CDC42-STE50-STE11-Pbs2 complex in Saccharomyces cerevisiae that is required for the regulation of p38 activity.
Uhlik
Mark T
MT
Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine Chapel Hill, NC 27599-7365, USA.
Abell
Amy N
AN
Johnson
Nancy L
NL
Sun
Weiyong
W
Cuevas
Bruce D
BD
Lobel-Rice
Katherine E
KE
Horne
Eric A
EA
Dell'Acqua
Mark L
ML
Johnson
Gary L
GL
D008841:Actin Cytoskeleton / Q000378:metabolism; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D001665:Binding Sites / Q000502:physiology; D019556:COS Cells; D022081:Cell Surface Extensions / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000302:isolation & purification*; D003599:Cytoskeleton / Q000378:metabolism*; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D006801:Humans; D048371:MAP Kinase Kinase 3; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D046911:Macromolecular Substances; D008840:Microfilament Proteins / Q000235:genetics / Q000302:isolation & purification*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009997:Osmotic Pressure; D011485:Protein Binding / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D013012:Sorbitol / Q000494:pharmacology; D014882:Water-Electrolyte Balance / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D046911:Macromolecular Substances; D008840:Microfilament Proteins; C480498:osmosensing scaffold for MEKK3 protein, mouse; D013012:Sorbitol; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; C482625:MAP3K3 protein, human; C482626:Map3k3 protein, mouse; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human; C482531:Map2k3 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D020744:rac GTP-Binding Proteins