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: C Oneyama, Y Yoshikawa, Y Ninomiya, T Iino, S Tsukita, M Okada
• Journal: Oncogene (Oncogene) Vol. 35 Issue 4 Pg. 501-12 (Jan 28 2016) ISSN: 1476-5594 [Electronic] England
• PMID: 25867068 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytoskeletal Proteins
• ezrin
• proto-oncogene protein c-fes-fps
• EGFR protein, human
• ErbB Receptors
• Protein-Tyrosine Kinases
• CSK Tyrosine-Protein Kinase
• src-Family Kinases
• CSK protein, human

Topics

• Animals
• CSK Tyrosine-Protein Kinase
• Cell Line, Tumor
• Cell Transformation, Neoplastic (metabolism)
• Colonic Neoplasms (metabolism, pathology)
• Cytoskeletal Proteins (metabolism)
• ErbB Receptors (metabolism)
• Focal Adhesions (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Mice, Inbred BALB C
• Phosphorylation
• Protein-Tyrosine Kinases (genetics, metabolism)
• Signal Transduction
• Xenograft Model Antitumor Assays
• src-Family Kinases (genetics, metabolism)