IQGAP1

IQGAP1 is a large scaffolding protein encoded by the IQGAP1 gene in humans. It belongs to the IQGAP family of IQ motif-containing GTPase-activating proteins. IQGAP1 functions as a cytosolic and cortical scaffold that coordinates signaling pathways and cytoskeletal dynamics by binding multiple partners, including the small GTPases Rac1 and Cdc42, actin, and various regulatory proteins. Although it contains a RasGAP-related domain, IQGAP1 lacks intrinsic GTPase-activating activity and instead acts as an effector that stabilizes active GTPases and links them to downstream pathways.

Structural features include an N-terminal calponin homology domain that binds F-actin, a central coiled-coil region, four C-terminal IQ motifs that bind calmodulin, and a RasGAP-related domain. This arrangement enables simultaneous interactions with actin, calmodulin, and GTPases, integrating signaling at adherent junctions and the leading edge.

IQGAP1 interacts with β-catenin and E-cadherin at adherens junctions, with CLIP170 and tubulin for microtubule dynamics, and with components of the MAPK cascade, contributing to ERK activation. It also associates with other proteins such as MENA and actin-regulatory factors to coordinate cytoskeletal remodeling. Through these interactions, IQGAP1 links extracellular cues to cytoskeletal rearrangements and signal transduction.

Expression is widespread with important roles in development, cell adhesion, and migration. Dysregulation of IQGAP1 has been linked to cancer progression and metastasis in various tumor types, where it can promote invasive behavior. Because of its central scaffolding function, IQGAP1 is a focus of research on therapies aimed at disrupting aberrant signaling networks in cancer. Related family members IQGAP2 and IQGAP3 share domain architecture and overlap in function but have distinct tissue distributions and roles.