The cysteine in the M/IXXCW motif is conserved in all but one (threonine in place of cysteine) of the human protein tyrosine kinases (PTKs). We showed that all RET-PTC-1 mutants in which the C in this motif (C376) was replaced with glycine, lysine, threonine or serine lost their activity in vitro. However, the C376T/S mutants showed normal tyrosine phosphorylation in vivo (in cells). Further analyses reveled that protein kinase C (PKC) initiated the activities of the C376T/S mutants in cells. We conclude that the M/IXXCW motif-mediated mechanisms which initiate PTK activities are partially replaced by a PKC-mediated mechanism.
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