Formation of protein kinase C(epsilon)-Lck signaling modules confers cardioprotection.
The epsilon isoform of protein kinase C (PKCepsilon) is a member of the PKC family of serine/threonine kinases and plays a critical role in protection against ischemic injury in multiple organs. Functional proteomic analyses of PKCepsilon signaling show that this isozyme forms multiprotein complexes in the heart; however, the precise signaling mechanisms whereby PKCepsilon orchestrates cardioprotection are poorly understood. Here we report that Lck, a member of the Src family of tyrosine kinases, forms a functional signaling module with PKCepsilon. In cardiac cells, PKCepsilon interacts with, phosphorylates, and activates Lck. In vivo studies showed that cardioprotection elicited either by cardiac-specific transgenic activation of PKCepsilon or by ischemic preconditioning enhances the formation of PKCepsilon-Lck modules. Disruption of these modules, via ablation of the Lck gene, abrogated the infarct-sparing effects of these two forms of cardioprotection, indicating that the formation of PKCepsilon-Lck signaling modules is required for the manifestation of a cardioprotective phenotype. These findings demonstrate, for the first time to our knowledge, that the assembly of a module (PKCepsilon-Lck) is an obligatory step in the signal transduction that results in a specific phenotype. Thus, PKCepsilon-Lck modules may serve as novel therapeutic targets for the prevention of ischemic injury.
Ping
Peipei
P
Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky, USA. peipeiping@hotmail.com
Song
Changxu
C
Zhang
Jun
J
Guo
Yiru
Y
Cao
Xinan
X
Li
Richard C X
RC
Wu
Wenjian
W
Vondriska
Thomas M
TM
Pass
Jason M
JM
Tang
Xian-Liang
XL
Pierce
William M
WM
Bolli
Roberto
R
D000818:Animals; D005260:Female; D019157:Ischemic Preconditioning, Myocardial; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000096:biosynthesis* / Q000235:genetics; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000201:enzymology / Q000517:prevention & control*; D010641:Phenotype; D011493:Protein Kinase C / Q000096:biosynthesis* / Q000235:genetics; D051744:Protein Kinase C-epsilon; D015398:Signal Transduction
D007527:Isoenzymes; D046911:Macromolecular Substances; C497256:Prkce protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon