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.
Highlights
The mammalian cell is under constant stimulation from its surroundings and needs to respond accurately and rapidly in order to function properly and survive
The interaction is mediated by the Proline Rich Domain (PRD) of MEK1 and MEK2, and is regulated by phosphorylation of Ser[298] in MEK1 or Ser[306], which we identified as a phosphorylation site in MEK2
We found that MEK1 and AKT interacted, and the number of interaction events is significantly increased upon 15′Epidermal Growth Factor (EGF) stimulation (Fig. 1E,F)
Summary
The mammalian cell is under constant stimulation from its surroundings and needs to respond accurately and rapidly in order to function properly and survive. The ERK1/2 cascade transmits its signals via a sequential phosphorylation and activation of a core three tires of protein kinases, Raf, MEK1/2, and ERK1/2 downstream of Ras[5,6]. The most prominent cross talk is seen in the upstream level as Ras was shown to activate the PI3K complex[31] via a direct interaction with its p110 catalytic subunit[32] This interaction can positively affect the ERK1/2 cascade[33,34]. Cross-activation between the two pathways was shown for PAK1, which is activated downstream to PI3K41, and directly phosphorylates MEK1 on Ser[298] in response to adhesion to fibronectin, leading to MEK1’s enhanced activation[42,43]. Pathway convergence can occur downstream of the two pathways as in some cases, both cascades can affect the same targets, as in the case of the transcription factor FoxO345 or the central translation regulating target mTORC146
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