Tyrosine phosphorylation modifies protein kinase C δ-dependent phosphorylation of cardiac troponin I

Marius P. Sumandea, Vitalyi O. Rybin, Aaron C. Hinken, Chaojian Wang, Tomoyoshi Kobayashi, Erin Harleton, Gail Sievert, C. William Balke, Steven J. Feinmark, R. John Solaro, Susan F. Steinberg

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Our study identifies tyrosine phosphorylation as a novel protein kinase Cδ (PKCδ) activation mechanism that modifies PKCδ-dependent phosphorylation of cardiac troponin I (cTnI), a myofilament regulatory protein. PKCδ phosphorylates cTnI at Ser23/Ser24 when activated by lipid cofactors; Src phosphorylates PKCδ at Tyr311 and Tyr332 leading to enhanced PKCδ autophosphorylation at Thr505 (its activation loop) and PKCδ-dependent cTnI phosphorylation at both Ser23/Ser24 and Thr144. The Src-dependent acquisition of cTnI-Thr144 kinase activity is abrogated by Y311F or T505A substitutions. Treatment of detergent-extracted single cardiomyocytes with lipid-activated PKCδ induces depressed tension at submaximum but not maximum [Ca2+] as expected for cTnI-Ser 23/Ser24 phosphorylation. Treatment of myocytes with Src-activated PKCδ leads to depressed maximum tension and cross-bridge kinetics, attributable to a dominant effect of cTnI-Thr144 phosphorylation. Our data implicate PKCδ-Tyr311/Thr 505 phosphorylation as dynamically regulated modifications that alter PKCδ enzymology and allow for stimulus-specific control of cardiac mechanics during growth factor stimulation and oxidative stress.

Original languageEnglish
Pages (from-to)22680-22689
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number33
DOIs
StatePublished - Aug 15 2008

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