Identification of a human epidermal growth factor receptor-associated protein kinase as a new member of the mitogen-activated protein kinase/extracellular signal-regulated protein kinase family

Williams, R.; Sanghera, J.; Wu, F.; Carbonaro-Hall, D.; Campbell, D.L.; Warburton, D.; Pelech, S.; Hall, F.

Journal of Biological Chemistry 268(24): 18213-18217


ISSN/ISBN: 0021-9258
PMID: 7688742
Accession: 008804969

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A putative mitogen-activated protein kinase (MAPK) has recently been identified, which potentially phosphorylates the human epidermal growth factor (EGF) receptor at a physiological site (Thr-669) and is distinguished from other MAPKs/extracellular signal-regulated protein kinases (ERKs) on the basis of chromatographic, immunological, and kinetic data. Here we report that this newly discovered MAPK is physically associated with the EGF receptor in A431 cells and with the related receptor/tyrosine kinase HER2 (encoded by c-neu) in enzyme preparations obtained from Wilm's tumors. This human EGF receptor-associated kinase is characterized as a 40-kDa Thr-669 kinase that exists in a high molecular mass complex with the respective growth factor receptor. EGF treatment of A431 cells stimulates the tyrosine phosphorylation of p40 and increases Thr-669 kinase activity in p40-containing fractions. The 40-kDa kinase is recognized by affinity-purified polyclonal antibodies directed against the sea star p44-mpk and a PanERK antibody directed against the conserved subdomain VIII of MAPKs/ERKs, but is not recognized b antibodies selective for the rat p44-erk1 and/or the p42-mapk/erk2 isoforms, thus identifying the EGF receptor associated kinase as a novel MAPK that may regulate receptor function in vivo.