title: Direct binding of MEK1 and MEK2 to AKT induces Foxo1 phosphorylation, cellular migration and metastasis.
abstract: Crosstalk between the ERK cascade and other signaling pathways is one of the means by which it acquires its signaling specificity. Here we identified a direct interaction of both MEK1 and MEK2 with AKT. The interaction is mediated by the proline rich domain of MEK1/2 and regulated by phosphorylation of Ser298 in MEK1, or Ser306 in MEK2, which we identified here as a novel regulatory site. We further developed a blocking peptide, which inhibits the interaction between MEK and AKT, and when applied to cells, affects migration and adhesion, but not proliferation. The specific mechanism of action of the MEK-AKT complex involves phosphorylation of the migration-related transcription factor FoxO1. Importantly, prevention of the interaction results in a decreased metastasis formation in a breast cancer mouse model. Thus, the identified interaction both sheds light on how signaling specificity is determined, and represents a possible new therapeutic target for metastatic cancer.
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shiri
authors.initials: S
authors.lastname: Procaccia
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Merav
authors.initials: M
authors.lastname: Ordan
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Izel
authors.initials: I
authors.lastname: Cohen
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Sarit
authors.initials: S
authors.lastname: Bendetz-Nezer
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Rony
authors.initials: R
authors.lastname: Seger
mesh_terms: D000818:Animals; D019556:COS Cells; D002465:Cell Movement; D002522:Chlorocebus aethiops; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; C482128:MAP2K2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human