The regulatory domain of protein kinase C delta positively regulates insulin receptor signaling

Avraham I. Jacob, Miriam Horovitz-Fried, Shlomit Aga-Mizrachi, Tamar Brutman-Barazani, Hana Okhrimenko, Yehiel Zick, Chaya Brodie, Sanford R. Sampson

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Protein kinase C delta (PKCδ) is induced by insulin to rapidly associate with insulin receptor (IR) and upregulates insulin signaling. We utilized specific JM and CT receptor domains and chimeras of PKCα and PKCδ regulatory and catalytic domains to elucidate which components of PKCδ are responsible for positive regulatory effects of PKCδ on IR signaling. Studies were performed on L6 and L8 skeletal muscle myoblasts and myotubes. PKCδ was preferentially bound to the JM domain of IR, and insulin stimulation increased this binding. Both PKCδ/α and PKCα/δ chimeras (regulatory/catalytic) were bound preferentially to the JM but not to the CT domain of IR. Although IR-PKCδ binding was higher in cells expressing either the PKCδ/α or PKCα/δ chimera than in control cells, upregulation of IR signaling was observed only in PKCδ/α cells. Thus, in response to insulin increases in tyrosine phosphorylation of IR and insulin receptor substrate-1, downstream signaling to protein kinase B and glycogen synthase kinase 3 (GSK3) and glucose uptake were greater in cells overexpressing PKCδ/α and the PKCδ/δ domains than in cells expressing the PKCα/δ domains. Basal binding of Src to PKCδ was higher in both PKCδ/α- and PKCα/δ-expressing cells compared to control. Binding of Src to IR was decreased in PKCα/δ cells but remained elevated in the PKCδ/α cells in response to insulin. Finally, insulin increased Src activity in PKCδ/α-expressing cells but decreased it in PKCα/δ-expressing cells. Thus, the regulatory domain of PKCδ via interaction with Src appears to determine the role of PKCδ as a positive regulator of IR signaling in skeletal muscle.

Original languageEnglish
Pages (from-to)155-169
Number of pages15
JournalJournal of Molecular Endocrinology
Issue number3
StatePublished - Mar 2010


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