EGF receptor mediates adhesion-dependent activation of the Rac GTPase: a role for phosphatidylinositol 3-kinase and Vav2

Abstract

Organization of the actin cytoskeleton in eucaryotic cells is controlled by small GTPases of the Rho family. Rac becomes activated by growth factor stimulation and integrin-mediated cell adhesion to extracellular matrix and is known to have a crucial role in lamellipodia formation, cell spreading and migration. At present, the intracellular pathways that connect cell surface receptors to Rac activation are poorly characterized. It has been reported previously that integrin-mediated cell attachment induces activation of the EGF receptor (EGFR) in the absence of EGF. We demonstrate here that this activation is instrumental for integrin-dependent Rac activation. Thus, we found that cells in which EGFR activity had been inhibited failed to spread and form lamellipodia on fibronectin. Failure to spread coincided with inhibition of adhesion-induced GTP loading of Rac and also with inhibition of the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Subsequent studies demonstrated that an activated form of PI 3-kinase restored Rac GTP loading in the presence of EGFR inhibition, while a dominant-negative form of PI 3-kinase blocked Rac GTP loading in fibronectin-adherent cells. Our further functional studies identified Vav2, a known exchange factor for Rac, as a crucial downstream component in EGFRand PI 3-kinase-dependent Rac activation upon integrinmediated cell adhesion. Our results provide a mechanistic insight into integrin-dependent Rac activation, and identify a novel role for EGFR, PI 3-kinase and Vav2 in this pathway.

Up-regulation of Rac1 by Epidermal Growth Factor Mediates COX-2 Expression in Recurrent Respiratory Papillomas

“…Rac1 transduces signals from both the EGFR and PI3K in other cell types (23,24,25), consistent with their contribution to COX-2 expression in papilloma cells (10). Slice et al (25) reported that signaling by small GTPases results in COX-2 expression in 3T3 cells through independent, parallel signaling pathways.…”

Simultaneous Blockade of Platelet-Derived Growth Factor-Receptor and Epidermal Growth Factor-Receptor Signaling and Systemic Administration of Paclitaxel as Therapy for Human Prostate Cancer Metastasis in Bone of Nude Mice

“…Blockade of EGF-R or PDGF-R can alter phosphatidylinositol 3Ј-kinase activity, leading to a change in interstitial fluid homeostasis, which results in a reduction of interstitial hypertension with an increase in transcapillary transport (72)(73)(74). The roles of EGF and PDGF in angiogenesis have been reported for several human tumors (75)(76)(77)(78), and destruction of the vasculature within neoplasms can produce necrosis of actively growing tumors (79,80).…”

High expression of integrin β6 in association with the Rho–Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers

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