title: PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation.
abstract: Activation of the Ras-MAPK signal transduction pathway is necessary for biological responses both to growth factors and ECM. Here, we provide evidence that phosphorylation of S298 of MAPK kinase 1 (MEK1) by p21-activated kinase (PAK) is a site of convergence for integrin and growth factor signaling. We find that adhesion to fibronectin induces PAK1-dependent phosphorylation of MEK1 on S298 and that this phosphorylation is necessary for efficient activation of MEK1 and subsequent MAPK activation. The rapid and efficient activation of MEK and phosphorylation on S298 induced by cell adhesion to fibronectin is influenced by FAK and Src signaling and is paralleled by localization of phospho-S298 MEK1 and phospho-MAPK staining in peripheral membrane-proximal adhesion structures. We propose that FAK/Src-dependent, PAK1-mediated phosphorylation of MEK1 on S298 is central to the organization and localization of active Raf-MEK1-MAPK signaling complexes, and that formation of such complexes contributes to the adhesion dependence of growth factor signaling to MAPK.
authors.affiliation: Department of Microbiology, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors.forename: Jill K
authors.initials: JK
authors.lastname: Slack-Davis
authors.forename: Scott T
authors.initials: ST
authors.lastname: Eblen
authors.forename: Maja
authors.initials: M
authors.lastname: Zecevic
authors.forename: Scott A
authors.initials: SA
authors.lastname: Boerner
authors.forename: Adel
authors.initials: A
authors.lastname: Tarcsafalvi
authors.forename: H Bruce
authors.initials: HB
authors.lastname: Diaz
authors.forename: Mark S
authors.initials: MS
authors.lastname: Marshall
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weber
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Parsons
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Catling
mesh_terms: D000818:Animals; D019556:COS Cells; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D005353:Fibronectins / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D022001:Focal Adhesions / Q000378:metabolism; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D054462:p21-Activated Kinases; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism
chemical_list: C412373:AG 1879; D015815:Cell Adhesion Molecules; D005353:Fibronectins; D011743:Pyrimidines; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496052:Ptk2 protein, rat; D019061:src-Family Kinases; C515906:Pak1 protein, rat; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D054462:p21-Activated Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases