Growth factor-stimulated MAP kinase induces rapid retrophosphorylation and inhibition of MAP kinase kinase (MEK1).
The MAP kinase module (Raf/MAPKKK-MAPKK-MAPK) has been shown to be sequentially activated after mitogenic stimulation. Here we demonstrate, by site directed mutagenesis, that MAPK is able to retrophosphorylate its own activator, MAPKK, on two threonine residues Thr-292 and Thr-386 in vitro, and that these sites are also phosphorylated in vivo. A comparison of the kinetics of serum-mediated activation of a wild-type MAPKK and of a mutant unable to undergo phosphorylation by MAPK suggests that this retrophosphorylation may be involved in a negative feedback control of the cascade in vivo.
Centre de Biochimie-CNRS, Université de Nice, France.
A
A
Brunet
G
G
Pagès
J
J
Pouysségur
D000818:Animals; D001665:Binding Sites; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D005246:Feedback; D006133:Growth Substances / Q000494:pharmacology*; D007163:Immunosorbent Techniques; D007700:Kinetics; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013912:Threonine / Q000235:genetics; D014162:Transfection
D006133:Growth Substances; D047428:Protein Kinase Inhibitors; D010769:Phosphothreonine; D013912:Threonine; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases