IQGAP1 is a phosphoinositide effector and kinase scaffold

Abstract

Phosphatidylinositol 4,5-bisphosphate (PI4,5P2) is a lipid messenger that regulates a wide variety of cellular functions. The majority of cellular PI4,5P2 is generated by isoforms of the type I phosphatidylinositol phosphate kinases (PIPKI) that are generated from three genes, and each PIPKI isoform has a unique distribution and function in cells. It has been shown that the signaling specificity of PI4,5P2 can be determined by a physical association of PIPKs with PI4,5P2 effectors. IQGAP1 is newly identified as an interactor of multiple isoforms of PIPKs. Considering the versatile roles of IQGAP1 in cellular signaling pathways, IQGAP1 may confer isoform-specific roles of PIPKs in distinct cellular locations. In this mini review, the emerging roles of PIPKs that are regulated by an association with IQGAP1 will be summarized. Focuses will be on cell migration, vesicle trafficking, cell signaling, and nuclear events.

Keywords: Cell signaling; IQGAP; Phosphatidylinositol phosphate kinase; Phosphoinositide.

Figure 1. A proposed mechanism of IQGAP1 activation

IQGAP1 folds into an inactive conformation by intramolecular interactions. Phosphorylation at serine 1443 residue relieves the N- and C-termini interaction. This phosphorylation also allows PIPKIγ binding on the IQ domain. Small GTPases Rac1 and Cdc42 binding on the GRD domain or PI4,5P₂ binding on RGCT domain further opens up IQGAP1 structure. The relieved RGCT domain recruits downstream effector proteins such as N-WASP, CLIP-170 and the exocyst complex.

Figure 2. Homology between IQGAP1 and IQGAP2

Both IQGAP1 and IQGAP2 contain five domains and each domain has different homology. Percent of identity is shown in the middle.