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 language | English |
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Pages (from-to) | 22680-22689 |
Number of pages | 10 |
Journal | Journal of Biological Chemistry |
Volume | 283 |
Issue number | 33 |
DOIs | |
State | Published - Aug 15 2008 |