Intracellular calcium regulates the tyrosine kinase receptor encoded by the MET oncogene

Lucia Gandino, Luca Munaron, Luigi Naldini, Riccardo Ferracini, Michele Magni, Paolo M. Comoglio

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Previous work (Gandino, L., Di Renzo, M. F., Giordano, S., Bussolino, F., and Comoglio, P. M. (1990) Oncogene 5, 721-725) has shown that the tyrosine kinase activity of the receptor encoded by the MET protooncogene is negatively modulated by protein kinase C (PKC). We now show that an increase of intracellular Ca2+ has a similar inhibitory effect in vivo, via a PKC-independent mechanism. In GTL-16 cells the p145MET kinase is overexpressed and constitutively phosphorylated on tyrosine. A rapid and reversible decrease of p145MET tyrosine phosphorylation was induced by treatment with the calcium ionophores A23187 or ionomycin. Experiments performed with the ionophores in absence of extracellular calcium showed that a rise in cytoplasmic Ca2+ concentration to 450 nM (due to release from intracellular stores) resulted in a similar effect. These Ca2+ concentrations had no effect on p145MET autophosphorylation in an in vitro kinase assay. This suggests that the effect of Ca2+ on p145MET tyrosine phosphorylation is not direct but may be mediated by Ca2+-activated protein(s). Involvement of Ca2+-dependent tyrosine phosphatases was ruled out by experiments carried out in presence of Na3VO4. In vivo labeling with [32P]orthophosphate showed that the rise of intracellular Ca2+ induces serine phosphorylation of p145MET on a specific phosphopeptide. This suggests that Ca2+ negatively modulates p145MET kinase through the phosphorylation of a critical serine residue by a Ca2+-activated serine kinase distinct from PKC.

Original languageEnglish
Pages (from-to)16098-16104
Number of pages7
JournalJournal of Biological Chemistry
Issue number24
Publication statusPublished - 1991

ASJC Scopus subject areas

  • Biochemistry


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