PI3K/Akt signaling is fundamental in the immune system, cardiovascular and neuronal diseases, and cancers. It is the most commonly deregulated signaling pathway in cancers and is therapeutically targeted. We show that the multi-domain scaffolding oncoprotein, IQGAP1 provides a novel molecular platform for assembly of PI4P-, PI4,5P2- and PI3,4,5P3-generating enzymes (PI4KIII?, PIPKI? and PI3K). This close proximity allows for concerted and efficient generation of the PI3,4,5P3 lipid messenger that activates the also associated PDK1/Akt kinases. Multiple agonists including integrins, receptor tyrosine kinases and G-protein coupled receptors stimulate this scaffold. Importantly, this scaffold appears crucial for cancer cell survival, uncovering a phosphoinositide signaling nexus utilized by cancer cells for their survival. IQGAP1 associates with PI3K and PIPKI? via its WW and IQ sub-domains. Disrupting this IQGAP1 scaffold abrogates PI3,4,5P3 generation and Akt activation and selectively blocks survival of cancer cells. This indicates that concerted PI3,4,5P3 synthesis with PDK1 and Akt activation in cancer cells via the IQGAP1 scaffold opens the door for novel therapeutic strategy targeting PI3K/Akt signaling in cancers. Further, IQGAP2 has tumor suppressor activity and also binds the PIPn kinases blocks Akt activation within the same pathways. Hypothesis: Upon agonist stimulation, IQGAP1 scaffolds phosphoinositide kinases for concerted production of the PI3,4,5P3 lipid messenger, leading to self-contained PI3K/Akt signaling platform. Selective integration of PIPKI isoforms (e.g. PIPKI? vs. PIPKI?) into IQGAP1 scaffolds and their regulation of PI4,5P2 and/or PI3,4,5P3 generation and downstream activation controls distinct processes including cell proliferation, survival, invasion and motility. IQGAP2 binding to the PIPn kinases blocks the tumor promoting activity of the PIPn kinases. This hypothesis will be interrogated with the following aims:
Aim 1. How does EGF-stimulation specifically assemble the IQGAP1-PI3K scaffold? (a) Role of tyrosine phosphorylation, (b) define interaction sites, substrate channeling, and identify mutants that lose binding and study integration of oncogenic PI3K mutants, and (c) examine if these require EGFR signaling.
Aim 2. Study how EGFR and small G-proteins regulate IQGAP1-PIPn kinase scaffolds during migration and invasion. Roles of: (a) the IQGAP1-PI3K scaffold in cell motility, (b) the IQGAP1-PIPKI? scaffold in trafficking of EGFR and integrins in EGF-stimulated migration and invasion, (c) IQGAP1 in Arf6 and Rac1 in control of invasion and (d) study the role of PIPn binding to IQGAP1 in spatial targeting, survival, and invasion.
Aim 3. Investigate the IQGAP2-phosphoinositide kinase scaffold as a tumor suppressor. (a) Study interactions of phosphoinositide kinases with IQGAP2 and peptide inhibitors will be developed, (b) define the mechanism how IQGAP2 blocks Akt activation, (c) manipulate expression of IQGAP2 to examine roles in the PI3K signaling and biology.

Public Health Relevance

The agonist activated PI3K have roles in many biological functions including in the immune system, cardiovascular and neuronal diseases, and cancers. Here we have identified a novel scaffolded PI3K pathway where all of the enzymes required for generation of the second messenger phosphatidylinositol-3,4,5- trisphosphate are assembled. Further, the downstream protein kinases that control the signaling of this key agonist stimulated pathway are also assembled on the scaffold, indicating that this is a key therapeutic target for anticancer treatment and this is validated as short peptides that block the scaffold assembly selectively kill cancer cells.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Phillips, Andre W
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University of Wisconsin Madison
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