Fyn is induced by Ras/PI3K/Akt signaling and is required for enhanced invasion/migration

Src family kinases (SFKs) are frequently over‐expressed and/or activated in human cancers, and play key roles in cancer cell invasion, metastasis, proliferation, survival, and angiogenesis. Allosteric activation of SFKs occurs through well‐defined post‐translational mechanisms, however the SFK member Fyn is over‐expressed in multiple human cancers (prostate, melanoma, pancreatic, glioma, chronic myelogenous leukemia) and the mechanism of increased Fyn expression is unclear. Since activation of Ras oncogenes is a common oncogenic event leading to the activation of multiple effector pathways, we explored if Ras could induce Fyn expression. Retroviral transduction of the human keratinocyte cell line HaCaT with oncogenic H‐Ras dramatically up‐regulated Fyn mRNA (>100‐fold, P < 0.001), protein, and kinase activity without affecting Src levels or activity. Activation of Akt, but not MAPK or EGFR, was necessary and sufficient for induction of Fyn by H‐Ras. Expression of active Fyn was sufficient to increase HaCaT cell migration and invasion, and the enhanced migration and invasion induced by H‐Ras could be significantly blocked (70% reduction, P < 0.01) by knockdown of Fyn with a specific siRNA or inhibition of SFKs with PP2. In addition, expression of Fyn in MDA‐MB‐231 breast cancer cells was dependent on PI3K activity and was involved in their invasive phenotype. Thus, the Ras/PI3K/Akt pathway can account for Fyn over‐expression in cancers, and Fyn is a critical mediator of the Ras‐stimulated invasive cell phenotype. These results support the development of therapeutic strategies targeting Akt/Fyn pathway to block migration and invasion of tumor cells. Mol. Carcinog. © 2010 Wiley‐Liss, Inc.