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

被引:49
作者
Sumandea, Marius P. [2 ]
Rybin, Vitalyi O. [1 ]
Hinken, Aaron C. [3 ]
Wang, Chaojian [1 ]
Kobayashi, Tomoyoshi [3 ]
Harleton, Erin [1 ]
Sievert, Gail [2 ]
Balke, C. William [2 ]
Feinmark, Steven J. [1 ]
Solaro, R. John [3 ]
Steinberg, Susan F. [1 ]
机构
[1] Columbia Univ, Dept Pharmacol, Coll Phys & Surg, New York, NY 10032 USA
[2] Univ Kentucky, Cardiovasc Res Ctr, Dept Internal Med, Lexington, KY 40536 USA
[3] Univ Illinois, Dept Physiol & Biophys, Cardiovasc Res Ctr, Chicago, IL 60612 USA
关键词
D O I
10.1074/jbc.M802396200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Our study identifies tyrosine phosphorylation as a novel protein kinase C delta(PKC delta) activation mechanism that modifies PKC delta-dependent phosphorylation of cardiac troponin I (cTnI), a myofilament regulatory protein. PKC delta phosphorylates cTnI at Ser(23)/Ser(24) when activated by lipid cofactors; Src phosphorylates PKC delta at Tyr(311) and Tyr(332) leading to enhanced PKC delta autophosphorylation at Thr(505) (its activation loop) and PKC delta-dependent cTnI phosphorylation at both Ser(23)/Ser(24) and Thr(144). The Src-dependent acquisition of cTnI-Thr(144) kinase activity is abrogated by Y311F or T505A substitutions. Treatment of detergent-extracted single cardiomyocytes with lipid-activated PKC delta induces depressed tension at submaximum but not maximum [Ca2+] as expected for cTnI-Ser(23)/ Ser(24) phosphorylation. Treatment of myocytes with Src-activated PKC delta leads to depressed maximum tension and cross-bridge kinetics, attributable to a dominant effect of cTnI-Thr144 phosphorylation. Our data implicate PKC delta-Tyr311/ Thr505 phosphorylation as dynamically regulated modifications that alter PKC delta enzymology and allow for stimulus-specific control of cardiac mechanics during growth factor stimulation and oxidative stress.
引用
收藏
页码:22680 / 22689
页数:10
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