ERK signaling and Akt signaling are inversely correlated in some cancers. Yet, the precise molecular mechanism for cross‐inhibition remains unclear. In this issue of The EMBO Journal, Pan et al (2017) show that when Akt is on, its phosphorylated cytoplasmic substrate FOXO1 turns off ERK activity by reshaping the Ras‐ERK scaffold IQGAP1.
See also: C-W Pan et al
The Ras‐extracellular signal‐regulated kinase (ERK) and phosphoinositide 3‐kinase (PI3K)‐Akt signaling pathways are key mechanisms for controlling cell survival, proliferation, differentiation, metabolism, motility, stemness, and are often deregulated in human cancers (Mendoza et al, 2011). In response to agonist activation of receptors, these two pathways crosstalk to regulate common downstream functions. In principle, mechanisms of the crosstalk are either activating or inhibiting. A well‐studied activating mechanism is that Ras directly binds and allosterically activates PI3K (Burke & Williams, 2015). The Ras‐ERK and PI3K‐Akt pathways can also attenuate each other. This cross‐inhibition is often manifested when one pathway is blocked. For example, pharmacological inhibition of components of one pathway leads to activation of the other pathway in many different cancer types (Mendoza et al, 2011). Acquired activation of one pathway by inhibition of the other has been recognized as a major resistance mechanism of chemotherapy in cancers (Chandarlapaty et al, 2011; Mendoza et al, 2011). However, molecular details of cross‐inhibition are not fully understood. In a study published in this issue of The EMBO Journal, Pan et al (2017) demonstrate that in prostate cancer cells, Akt phosphorylates O‐class forkhead factors (FOXO), especially FOXO1 …
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