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bioRxiv · 10.1101/2024.08.14.608018

NOK promotes tumorigenesis through coordinating epidermal growth factor receptor to boost the downstream signaling in breast cancer

Wang, Y.·Zhang, B.·He, C.·Tian, B.·Liu, S.·Li, J.·Wang, J.·Yang, S.·Zhu, B.·Wang, X.·Chang, Z.·Cao, C.
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Abstract

BACKGROUNDEpidermal growth factor receptor (EGFR) forms a homodimer or heterodimer with other ErbB receptor family members to activate different downstream cytoplasmic signaling proteins during tumorigenesis. METHODSAdenovirus 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. RESULTSEGFR 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. CONCLUSIONSOur 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/608018v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@17b0078org.highwire.dtl.DTLVardef@5bfe6forg.highwire.dtl.DTLVardef@19d3d15org.highwire.dtl.DTLVardef@155fc4_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIEGFR 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. C_LIO_LINOK enhances EGF signaling activation, in particular, the phosphorylation of STAT3, STAT5 and Erk1/2 via its JM domain. C_LIO_LINOK and EGFR synergistically promote proliferation and migration of breast cancer cells and induce tumorigenesis of normal cells. C_LIO_LICo-expression of NOK and EGFR correlates with tumor malignant stages in breast cancer patients. C_LI

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Wang, Y., Zhang, B., He, C., Tian, B., Liu, S., Li, J., Wang, J., Yang, S., Zhu, B., Wang, X., Chang, Z., Cao, C.. 2024-08-15. NOK promotes tumorigenesis through coordinating epidermal growth factor receptor to boost the downstream signaling in breast cancer. https://doi.org/10.1101/2024.08.14.608018

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