title: c-Src is required for tropomyosin receptor kinase C (TrkC)-induced activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway.
abstract: TrkC mediates many aspects of growth and development in the central nervous system. TrkC is expressed in a variety of non-neuronal tissues as well as human cancers. TrkC overexpression may drive tumorigenesis, invasion, and metastatic capability in cancer cells. However, relatively little is known about whether TrkC activity is also essential to maintain the malignant properties in human tumors. TrkC expression leads to the constitutive activation of two major effector pathways, namely the Ras-MAP kinase (MAPK) mitogenic pathway and the phosphatidylinositol 3-kinase (PI3K)-AKT pathway mediating cell survival. However, it remains unclear how TrkC activates Ras-Erk1/2 and/or PI3K-Akt cascades. Here we define some aspects of the molecular mechanisms regulating TrkC-dependent Ras-Erk1/2 and PI3K/Akt activation. We show that endogenous TrkC associated with c-Src in human and mouse cancer cells which express TrkC. TrkC-c-Src complexes were also detected in primary human breast cancer tissues. Suppression of c-Src by RNA interference in highly metastatic 4T1 mammary cancer cells, which express endogenous TrkC, resulted in markedly decreased expression of cyclin D1 and suppression of activation of Ras-Erk1/2 and PI3K-Akt. Moreover, inhibition of c-Src expression almost completely blocks colony formation of 4T1 cells in soft agar. Furthermore, in c-Src-deficient SYF cells, TrkC failed to activate the PI3K-Atk pathway, but not the Ras-Erk1/2 pathway. Therefore these data indicate that TrkC induces the PI3K-Akt cascade through the activation of c-Src.
authors.affiliation: Laboratory of Cell Regulation and Carcinogenesis, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon 406-840, Korea.
authors.forename: Wook
authors.initials: W
authors.lastname: Jin
authors.affiliation: Department of Pediatrics, Case Western Reserve University, The Ireland Cancer Center, Cleveland, Ohio 44106.
authors.forename: Chohee
authors.initials: C
authors.lastname: Yun
authors.affiliation: Yongdong Severance Hospital, Yonsei University, Kangnam, Seoul 135-720, Korea.
authors.forename: Joon
authors.initials: J
authors.lastname: Jeong
authors.affiliation: BRM Institute, Kangnam, Seoul 135-822, Korea.
authors.forename: Yangho
authors.initials: Y
authors.lastname: Park
authors.affiliation: Yongdong Severance Hospital, Yonsei University, Kangnam, Seoul 135-720, Korea.
authors.forename: Hy-De
authors.initials: HD
authors.lastname: Lee
authors.affiliation: Laboratory of Cell Regulation and Carcinogenesis, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon 406-840, Korea; Department of Pediatrics, Case Western Reserve University, The Ireland Cancer Center, Cleveland, Ohio 44106. Electronic address: jasonsjkim@gachon.ac.kr.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D020812:Receptor, trkC / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014410:Tumor Stem Cell Assay
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C526292:IRS1 protein, human; D007211:Indoles; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D034741:RNA, Small Interfering; C416927:SU 6656; D013449:Sulfonamides; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D020812:Receptor, trkC; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1