title: The tyrosine phosphatase SHP2 associates with CUB domain-containing protein-1 (CDCP1), regulating its expression at the cell surface in a phosphorylation-dependent manner.
abstract: CUB domain-containing protein-1 (CDCP1) is a transmembrane glycoprotein that is phosphorylated by SRC family kinases (SFK) before recruiting and activating PKCδ. CDCP1 is overproduced in many cancers. It promotes metastasis and resistance to anoïkis. The robust production of CDCP1 would be associated with stemness and has been proposed as a novel prognosis marker. The natural transmembrane location of CDCP1 makes it an ideal therapeutic target and treatments based on the use of appropriate antibodies are currently being evaluated. However, we still know very little about the molecular fate of CDCP1 and its downstream signaling events. Improvements in our understanding of the molecular events occurring downstream of CDCP1 are required to make use of changes of CDCP1 production or functions for therapeutic purposes. By the mean of co-immunoprecipitation and affinity precipitation we show here, for the first time, that CDCP1 interacts directly, with the cytosolic tyrosine phosphatase SHP2. Point mutants of CDCP1 show that residues Y734 and Y743 are responsible for its interaction with SHP2. It may therefore compete with SFK. We also demonstrate that a shRNA-mediated down regulation of SHP2 is associated with a stronger CDCP1 phosphorylation and an impairment of antibody-mediated CDCP1 internalization.
authors: Institut Curie, Normal and Pathological Development of Melanocytes, Orsay, France; Univ. Paris-Sud, Orsay, France; CNRS, UMR3347, Bat 110, Orsay, France; INSERM U1021, Bat 110, Orsay, France; Equipe labellisée-Ligue Nationale contre le Cancer, Orsay, France.
authors: Leslie Yewakon
authors: LY
authors: Gandji
authors: INSERM UMR-S972, Hôpital Paul Brousse, Villejuif, France.
authors: Richard
authors: R
authors: Proust
authors: Institut Curie, Normal and Pathological Development of Melanocytes, Orsay, France; Univ. Paris-Sud, Orsay, France; CNRS, UMR3347, Bat 110, Orsay, France; INSERM U1021, Bat 110, Orsay, France; Equipe labellisée-Ligue Nationale contre le Cancer, Orsay, France.
authors: Lionel
authors: L
authors: Larue
authors: Institut Curie, Normal and Pathological Development of Melanocytes, Orsay, France; Univ. Paris-Sud, Orsay, France; CNRS, UMR3347, Bat 110, Orsay, France; INSERM U1021, Bat 110, Orsay, France; Equipe labellisée-Ligue Nationale contre le Cancer, Orsay, France.
authors: Franck
authors: F
authors: Gesbert
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism*; D000951:Antigens, Neoplasm; D015153:Blotting, Western; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C432044:CDCP1 protein, human; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins; D014443:Tyrosine; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11