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CADM1 suppresses c-Src activation by binding with Cbp on membrane lipid rafts and intervenes colon carcinogenesis

Yumi Tsuboi1, Masaaki Oyama2, Hiroko Kozuka-Hata2

  • 1Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Biochemical and Biophysical Research Communications
|July 4, 2020
PubMed

Insights

Cell adhesion molecule 1 (CADM1) and Csk-binding protein (Cbp) suppress colon cancer by inhibiting oncogenic Src signaling. Loss of CADM1 and Cbp correlates with advanced tumor size and metastasis.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • Cell adhesion molecules (CAMs) function as tumor suppressors, primarily through cell attachment.
  • Additional mechanisms involving signal transduction modification are implicated in CAM tumor suppression.
  • Cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, mediates cell adhesion and acts as a tumor suppressor.

Purpose of the Study:

  • To comprehensively identify CADM1-associated proteins using proteomic analysis.
  • To investigate the functional interaction between CADM1, Csk-binding protein (Cbp), and c-Src signaling in colon cancer.
  • To determine the clinical relevance of CADM1 and Cbp expression in human colon cancer.

Main Methods:

  • Proteomic analysis of CADM1 immune-precipitates using mass spectrometry.
  • Co-immunoprecipitation assays to detect protein interactions (CADM1, Cbp, c-Src).
  • siRNA-mediated suppression and co-replacement of CADM1 and Cbp in colon cancer cell lines.
  • In vivo tumorigenicity assays in nude mice.

Main Results:

  • Csk-binding protein (Cbp) was identified as a CADM1-binding partner.
  • CADM1 and Cbp co-localize with c-Src in detergent-resistant membrane fractions.
  • Suppression of CADM1 enhances c-Src activation, while co-replacement of CADM1 and Cbp suppresses c-Src activation, wound healing, and tumorigenicity.
  • Loss of CADM1 and Cbp expression was observed in 55% and 83% of human colon cancers, respectively, correlating with tumor size and lymph node metastasis.

Conclusions:

  • CADM1 functions as a colon tumor suppressor by interacting with Cbp to inhibit oncogenic c-Src signaling, in addition to its cell adhesion activity.
  • The CADM1-Cbp complex plays a critical role in suppressing colon cancer progression.
  • Downregulation of CADM1 and Cbp is a significant event in human colon carcinogenesis.
Keywords:
CADM1CbpColon cancerSrcTumorigenesis

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