CUB-domain-containing protein 1 overexpression in solid cancers promotes cancer cell growth by activating Src family kinases.
The transmembrane glycoprotein, CUB (complement C1r/C1s, Uegf, Bmp1) domain-containing protein 1 (CDCP1) is overexpressed in several cancer types and is a predictor of poor prognosis for patients on standard of care therapies. Phosphorylation of CDCP1 tyrosine sites is induced upon loss of cell adhesion and is thought to be linked to metastatic potential of tumor cells. Using a tyrosine-phosphoproteomics screening approach, we characterized the phosphorylation state of CDCP1 across a panel of breast cancer cell lines. We focused on two phospho-tyrosine pTyr peptides of CDCP1, containing Tyr707 and Tyr806, which were identified in all six lines, with the human epidermal growth factor 2-positive HCC1954 cells showing a particularly high phosphorylation level. Pharmacological modulation of tyrosine phosphorylation indicated that, the Src family kinases (SFKs) were found to phosphorylate CDCP1 at Tyr707 and Tyr806 and play a critical role in CDCP1 activity. We demonstrated that CDCP1 overexpression in HEK293 cells increases global phosphotyrosine content, promotes anchorage-independent cell growth and activates several SFK members. Conversely, CDCP1 downregulation in multiple solid cancer cell lines decreased both cell growth and SFK activation. Analysis of primary human tumor samples demonstrated a correlation between CDCP1 expression, SFK and protein kinase C (PKC) activity. Taken together, our results suggest that CDCP1 overexpression could be an interesting therapeutic target in multiple solid cancers and a good biomarker to stratify patients who could benefit from an anti-SFK-targeted therapy. Our data also show that multiple tyrosine phosphorylation sites of CDCP1 are important for the functional regulation of SFKs in several tumor types.
Novartis Institutes for BioMedical Research, Basel, Switzerland.
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Leroy
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
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Shen
Novartis Institutes for BioMedical Research, Basel, Switzerland.
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Strande
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
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Meyer
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
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McLaughlin
Novartis Institutes for BioMedical Research, Basel, Switzerland.
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Lezan
Friedrich Miescher Institute, Basel, Switzerland.
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Bentires-Alj
Novartis Institutes for BioMedical Research, Basel, Switzerland.
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Voshol
Novartis Institutes for BioMedical Research, Basel, Switzerland.
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Bonenfant
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
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Alex Gaither
D015703:Antigens, CD / Q000235:genetics*; D000951:Antigens, Neoplasm; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D010766:Phosphorylation / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics; D014443:Tyrosine / Q000235:genetics; D019061:src-Family Kinases / Q000235:genetics*
D015703:Antigens, CD; D000951:Antigens, Neoplasm; C432044:CDCP1 protein, human; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins; D014443:Tyrosine; D004815:Epidermal Growth Factor; D019061:src-Family Kinases; D011493:Protein Kinase C