title: Fyn is induced by Ras/PI3K/Akt signaling and is required for enhanced invasion/migration.
abstract: 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.
authors.affiliation: Molecular Biology Program, Loyola University Chicago, Maywood, Illinois, USA.
authors.forename: Vipin
authors.initials: V
authors.lastname: Yadav
authors.forename: Mitchell F
authors.initials: MF
authors.lastname: Denning
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C412373:AG 1879; D011743:Pyrimidines; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins