Fig. 1.

IQGAP1 Scaffold as a Common Target in glioblastoma. A. Schematic Structure of IQGAP1 and Some Glioblastoma Relevant Partners. IQGAP1 is a ubiquitous modular signaling protein that nucleates many cellular pathways. It binds a variety of receptors, including EGFR1/HER1, VEGFR, PDGFRβ, and ERα. It also binds and regulates the activities of several kinases, including the mTOR/Akt1/PI3K and the MAPK pathways. Having a nuclear localization signal (NLS) at its C-terminus, it also plays roles in the nucleus. CHD denotes the calponin homology domain; IR-WW is the IQGAP1 repeats (IR) and proline-rich (WW) region involved in protein-protein interactions; IQ denotes the isoleucine and glutamine rich region that binds calcium-calmodulin and many other proteins; GRD is the Ras-GTPase related domain that bind small GTPases like Cdc42; RGCt is the Ras GAP C-terminal domain that engages multiple protein partners some of which are indicated on the drawing. As IQGAP1 modulates many cellular functions, its dysfunction has been implicated in many human diseases, including GB. B.A Proposed Model for IQGAP1 as a Common Clinical Target in Glioblastoma. IQGAP1 serves as a scaffold of most of the molecules and pathways that have been largely implicated in GB, particularly EGFR, MAPK, PI3K/Akt1/mTOR, and YAP/TAZ. Receptor-mediated endocytosis across the BBB [88] in vivo has been demonstrated for a few peptides [89] such as insulin, insulin-like receptor, transferrin, and EGFR [90], all of which are IQGAP1-binding partners [22, 76]. Further, previous studies have shown that caffeine, antidepressants, and anti-schizophrenia drugs can cross into the BBB [91]. Accordingly, IQGAP1 pharmacological inhibitors such as Haldol [92] or inhibitory peptides such as the IR-WW fragment will have a facile route to the GB tumors, potentially making targeting IQGAP1 a more effective strategy