NOK promotes tumorigenesis through coordinating epidermal growth factor receptor to boost the downstream signaling in breast cancer
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BACKGROUND
Epidermal growth factor receptor (EGFR) forms a homodimer or heterodimer with other ErbB receptor family members to activate different downstream cytoplasmic signaling proteins during tumorigenesis.
METHODS
Adenovirus and lentivirus were used to overexpress or deplete NOK and/or EGFR to evaluate the phosphorylation of EGFR, the interaction of NOK-EGFR and their role in cell proliferation and metastasis.
RESULTS
EGFR heterodimerizes with NOK (also known as STYK1), a novel tyrosine kinase with a transmembrane domain, to promote tumorigenesis and metastasis of breast cancer cells. We found that NOK directly interacted with EGFR and formed a heterodimer complex. Depletion of NOK impaired, but over-expression of NOK increased, the phosphorylation of EGFR. NOK enhanced EGF signaling activation, in particular, the phosphorylation of STAT3, STAT5 and Erk1/2 via its juxtamembrane (JM) domain in promoting the proliferation and migration of breast cancer cells. Overexpression of NOK and EGFR synergistically induced the tumorigenesis of NIH-3T3 normal cells. We finally demonstrated that co-expression of NOK and EGFR correlated with tumor malignant stages in breast cancer patients.
CONCLUSIONS
Our findings uncover a mechanism by which NOK coordinates EGFR to enhance EGF signaling during tumorigenesis and metastasis and propose a potential strategy for targeting NOK-EGFR in breast cancer treatment.
GRAPHICAL ABSTRACT
EGFR heterodimerizes with NOK/STYK1, a novel tyrosine kinase with a transmembrane domain, in a manner of cross interaction via their juxtamembrane (JM) domains and kinase domains.
NOK enhances EGF signaling activation, in particular, the phosphorylation of STAT3, STAT5 and Erk1/2 via its JM domain.
NOK and EGFR synergistically promote proliferation and migration of breast cancer cells and induce tumorigenesis of normal cells.
Co-expression of NOK and EGFR correlates with tumor malignant stages in breast cancer patients.
