title: Ligand-independent activation of MET through IGF-1/IGF-1R signaling.
abstract: The receptor tyrosine kinase, MET, has been implicated in tumorigenesis and metastasis of many solid tumors, by multiple mechanisms, including cross talk with epidermal growth factor receptor. In this study, we examined the role of insulin-like growth factor receptor-1 (IGF-1R) signaling in MET activation, focusing on prostate cancer cells. Stimulation of the prostate cancer cell line PC3 with IGF-1 induces a delayed phosphorylation of MET at multiple sites (indicative of full activation), reaching a maximum 18 hr after IGF-1 addition. MET activation does not require the sole MET ligand hepatocyte growth factor (HGF), but does require transcription to occur. Furthermore, direct injection of IGF-1 is sufficient to induce MET activation in vivo, in a PC3 xenograft model. Pharmacologic or genetic inhibition of the tyrosine kinase, Src, abolishes MET phosphorylation, and expression of activated Src is sufficient to induce Met phosphorylation in the absence of IGF-1 stimulation. Activated MET is essential for IGF-1-mediated increased migration of PC3 cells, demonstrating an important biologic effect of IGF-1-mediated MET activation. Finally, we demonstrate that IGF-1-induced delayed MET activation occurs in multiple cell lines which express both the receptors, suggesting that IGF-1R-mediated MET activation may contribute to tumorigenic properties of multiple cancer types when both growth factor receptors are expressed. The results further suggest that MET may be activated by multiple receptor tyrosine kinase receptors, and dual targeting of these receptors may be important therapeutically.
authors.affiliation: Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Varkaris
authors.forename: Sanchaika
authors.initials: S
authors.lastname: Gaur
authors.forename: Nila U
authors.initials: NU
authors.lastname: Parikh
authors.forename: Jian H
authors.initials: JH
authors.lastname: Song
authors.forename: Farshid
authors.initials: F
authors.lastname: Dayyani
authors.forename: Jung-Kang
authors.initials: JK
authors.lastname: Jin
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D016023:Integrins / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016023:Integrins; D008024:Ligands; D034741:RNA, Small Interfering; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D017526:Receptor, IGF Type 1; D019061:src-Family Kinases
keywords: IGF-1R; MET; Src; cross talk; prostate cancer