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.

Retracted: MicroRNA‐497 accelerates apoptosis while inhibiting proliferation, migration, and invasion through negative regulation of the MAPK/ERK signaling pathway via RAF‐1

“…Among all miRNAs, miR‐497 has been recognized as a tumor‐associated miRNA in breast cancer, colorectal carcinoma, and lung cancer, but the biological function of it in CC is not defined (Gu et al, ; Hu, Xu, & Ge, ; Jiang, Meng, Qi, Shen, & Sun, ). Now, we have already known that RAF‐1 was identified as one of the novel direct targets of miR‐195 and miR‐497, and that the extracellular signal‐regulated kinase 1 (ERK1) was one of the major signaling pathways which activate in a large number of cells (Li et al, ; Procaccia, Ordan, Cohen, Bendetz‐Nezer, & Seger, ). Mitogen‐activated protein kinase (MAPK) signaling pathway participated in tumor development, in which RAF‐1 and ERK1/2 are of great importance (Li et al, ).…”

Goserelin promotes the apoptosis of epithelial ovarian cancer cells by upregulating forkhead box�O1 through the PI3K/AKT signaling pathway

“…The FOXO transcription factors are considered to be tumor suppressors that inhibit cell proliferation and induce apoptosis ( 21 ). Indeed, FOXO1 plays multiple roles in various types of human cancers, including skin ( 23 ), liver ( 24 ) and breast cancer ( 25 ). An increasing number of studies have linked the tumor suppressor activity of FOXOs to the regulation of genes involved in cell death (e.g., Fasl) ( 26 ) and cell cycle arrest (e.g., p27 KIP1 ) ( 27 ).…”

Deciphering the roles of FOXO1 in human neoplasms

“…Cell culture experiments demonstrated that FOXO1 overexpression by transfection of the FOXO1‐AAA mutant gene suppresses NF‐κB signaling and gastric carcinogenesis . At the molecular level, Procaccia's group discovered that direct binding of MEK1 and MEK2 to Akt induces FOXO1 phosphorylation and thus contributes to cell migration and metastasis in a mouse breast cancer model . These findings all demonstrate that low levels/activity of FOXO1 is a possible factor for early carcinogenesis, and activated FOXO1 can inhibit carcinogenesis (Figs.…”

“…Previous studies have demonstrated that low levels or activity of FOXO1 have a close relationship with tumorigenesis. 34,35 FOXO1 silencing is related to suppressed EMT in A549 lung adenocarcinoma epithelial cells, which is evidenced by decreased epithelial markers (E-cadherin) and enhanced mesenchymal markers (SNAIL, SLUG). 36 Helicobacter pylori infection is the major risk factor for gastric cancer.…”