Views And Akt - ion ! IQGAP 1 in control of signaling pathways

T he Ras-extracellular signal-regulated kinase (ERK) and phosphoinositide 3kinase (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 RasERK 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 among other members. Phosphorylated FOXO1 localized in the cytoplasm binds to IQGAP1, a scaffold protein for the Ras-ERK pathway, and this disrupts scaffold assembly leading to inhibition of ERK activity (Fig 1). This novel mechanism of cross-inhibition of the RasERK and PI3K-Akt pathways is further supported clinically by showing that FOXO1 expression is inversely correlated with ERK activation in human prostate cancer biopsies. Moreover, the authors show that a small FOXO1-derived phosphorylationmimetic peptide has therapeutic effect to overcome chemoresistance in cancers (Pan et al, 2017). IQ motif containing GTPase-activating protein 1 (IQGAP1) is a multidomain protein that scaffolds multiple signaling pathways (Smith et al, 2015). The scaffold role of IQGAP1 is emerging as key in the Ras-ERK, Wnt, integrin, and PI3K-Akt pathways. For example, in the Ras-ERK pathway, Raf, MEK, and ERK interact with IQGAP1, which physically links the kinases in close proximity to facilitate their sequential phosphorylation (Ren et al, 2007). Recently, a scaffold role for IQGAP1 in the PI3K-Akt pathway has been revealed (Choi et al, 2016). In response to receptor activation, PI4KIIIa, PIPKIa, and PI3K are assembled by IQGAP1 and this results in sequential generation of phosphatidylinositol-3,4,5-trisphosphate (PI3,4,5P3) from phosphatidylinositol. PI3,4,5P3 effectors, phosphoinositide-dependent kinase 1 (PDK1), and Akt also assemble in the IQGAP1 complex. Pan et al (2017) now further show that a downstream target of Akt, FOXO1, also is in the IQGAP1 complex. FOXO1 acts as a transcription factor in the nucleus, but is degraded in the cytoplasm upon Akt-mediated phosphorylation. The study by Pan et al (2017) attributes a role to cytoplasmic, phosphorylated FOXO1 in the context of signaling, as p-FOXO1 binds IQGAP1, thereby promoting inhibition of Ras-ERK signaling. This suggests that the IQGAP1 multienzyme complex streamlines the synthesis of the lipid signal PI3,4,5P3 and that PI3,4,5P3 is then directly handed off to Akt and FOXO1 leading to their activation (Fig 1). In the phosphoinositide signal transduction pathways, the synthesis of lipid signals are tightly linked to its usage as the lipid signals rapidly diffuse in cellular membranes (Choi et al, 2015). Binding of FOXO1 to the IQGAP1-Akt complex might be another example of such proximitydependent mechanism. Pan et al (2017) clearly show that depletion of IQGAP1 reduces both ERK and Akt activation, further supporting that IQGAP1 scaffolds both the Ras-ERK and PI3K-Akt pathways. Of note, binding sites of each pathway components on IQGAP1 are overlapping. For example, ERK and PI3K both bind to the WW domain, and MEK and PIPKIa both bind to the IQ domain (Hedman et al, 2015; Choi et al, 2016). This supports that the two pathway components compete for binding to IQGAP1, and that IQGAP1dependent ERK or Akt activation is mutually exclusive. In agreement, Pan et al (2017) demonstrate that binding of Akt-phosphorylated FOXO1 to IQGAP1’s coiled-coil (CC) domain induces conformational changes, facilitating dissociation of Raf, MEK, and ERK from the IQGAP1 scaffold (Fig 1).