Abstract
Focal adhesions are specialized sites of cell attachment to the extracellular matrix where integrin receptors link extracellular matrix to the actin cytoskeleton, and they are constantly remodeled during cell migration. Focal adhesion kinase (FAK) is an important regulator of focal adhesion remodeling. AGAP2 is an Arf GTPase-activating protein that regulates endosomal trafficking and is overexpressed in different human cancers. Here we examined the regulation of the FAK activity and the focal adhesion remodeling by AGAP2. Our results show that FAK binds the pleckstrin homology domain of AGAP2, and the binding is independent of FAK activation following epidermal growth factor receptor stimulation. Overexpression of AGAP2 augments the activity of FAK, and concordantly, the knockdown of AGAP2 expression with RNA interference attenuates the FAK activity stimulated by epidermal growth factor or platelet-derived growth factor receptors. AGAP2 is localized to the focal adhesions, and its overexpression results in dissolution of the focal adhesions, whereas knockdown of its expression stabilizes them. The AGAP2-induced dissolution of the focal adhesions is independent of its GTPase-activating protein activity but may involve its N-terminal G protein-like domain. Our results indicate that AGAP2 regulates the FAK activity and the focal adhesion disassembly during cell migration.
Highlights
We find that AGAP2 forms a complex with Focal adhesion kinase (FAK), increases the FAK activity, and provokes the focal adhesion disassembly that may lead to increased cell migration
AGAP2 Forms a Complex with FAK—AGAP2 was shown to express at elevated levels in different human cancers, including
AGAP2 bound other components of the focal adhesions, we examined the possible co-immunoprecipitation of paxillin with
Summary
GST fusion proteins containhypothesized that AGAP2 regulates focal adhesions and cell ing the PH2 domain of AGAP2 successfully precipitated FAK. We examined the possible interac- The binding of FAK to AGAP2 was independent of cell type as tion of AGAP2 with the known regulators of the focal adhesions similar results were obtained using HEK293 and the breast car-
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