title: Fer tyrosine kinase oligomer mediates and amplifies Src-induced tumor progression.
abstract: c-Src is upregulated in various human cancers, suggesting its role in malignant progression. However, the molecular circuits of c-Src oncogenic signaling remain elusive. Here we show that Fer tyrosine kinase oligomer mediates and amplifies Src-induced tumor progression. Previously, we showed that transformation of fibroblasts is promoted by the relocation of c-Src to non-raft membranes. In this study, we identified Fer and ezrin as non-raft c-Src targets. c-Src directly activated Fer by initiating its autophosphorylation, which was further amplified by Fer oligomerization. Fer interacted with active c-Src at focal adhesion membranes and activated Fer-phosphorylated ezrin to induce cell transformation. Fer was also crucial for cell transformation induced by v-Src or epidermal growth-factor receptor activation. Furthermore, Fer activation was required for tumorigenesis and invasiveness in some cancer cells in which c-Src is upregulated. We propose that the Src-Fer axis represents a new therapeutic target for treatment of a subset of human cancers.
authors: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors: C
authors: C
authors: Oneyama
authors: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors: Y
authors: Y
authors: Yoshikawa
authors: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors: Y
authors: Y
authors: Ninomiya
authors: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors: T
authors: T
authors: Iino
authors: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan.
authors: S
authors: S
authors: Tsukita
authors: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors: M
authors: M
authors: Okada
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D003598:Cytoskeletal Proteins; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; D000099149:Ezrin; C052602:proto-oncogene protein c-fes-fps; C512478:EGFR protein, human; C000631346:CSK protein, human