PMID- 36112502
OWN - NLM
STAT- MEDLINE
DCOM- 20221006
LR  - 20231002
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 323
IP  - 4
DP  - 2022 Oct 1
TI  - Lipid-independent activation of a muscle-specific PKCalpha splicing variant.
PG  - H825-H832
LID - 10.1152/ajpheart.00304.2022 [doi]
AB  - Protein kinase C-alpha (PKCalpha) plays a major role in a diverse range of cellular 
      processes. Studies to date have defined the regulatory controls and function of 
      PKCalpha entirely based upon the previously annotated ubiquitously expressed 
      prototypical isoform. From RNA-seq-based transcriptome analysis in murine heart, 
      we identified a previously unannotated PKCalpha variant produced by alternative RNA 
      splicing. This PKCalpha transcript variant, which we named PKCalpha-novel exon (PKCalpha-NE), 
      contains an extra exon between exon 16 and exon 17, and is specifically detected 
      in adult mouse cardiac and skeletal muscle, but not other tissues; it is also 
      detected in human hearts. This transcript variant yields a PKCalpha isoform with 
      additional 16 amino acids inserted in its COOH-terminal variable region. Although 
      the canonical PKCalpha enzyme is a lipid-dependent kinase, in vitro kinase assays 
      show that PKCalpha-NE displays a high level of basal lipid-independent catalytic 
      activity. Our unbiased proteomic analysis identified a specific interaction 
      between PKCalpha-NE and eukaryotic elongation factor-1alpha (eEF1A1). Studies in 
      cardiomyocytes link PKCalpha-NE expression to an increase in eEF1A1 phosphorylation 
      and elevated protein synthesis. In summary, we have identified a previously 
      uncharacterized muscle-specific PKCalpha splicing variant, PKCalpha-NE, with distinct 
      biochemical properties that plays a unique role in the control of the protein 
      synthesis machinery in cardiomyocytes.NEW & NOTEWORTHY PKCalpha is an important 
      signaling molecule extensively studied in many cellular processes. However, no 
      isoforms have been reported for PKCalpha except one prototypic isoform. Alternative 
      mRNA splicing of Prkca gene was detected for the first time in rodent and human 
      cardiac tissue, which can produce a previously unknown PKCalpha-novel exon (NE) 
      isoform. The biochemistry and molecular effects of PKCalpha-NE are markedly different 
      from PKCalpha wild type, suggesting potential functional diversity of PKCalpha signaling 
      in muscle.
FAU - Gao, Chen
AU  - Gao C
AUID- ORCID: 0000-0001-7883-3270
AD  - Department of Pharmacology and System Physiology, University of Cincinnati, 
      Cincinnati, Ohio.
FAU - Gong, Jianli
AU  - Gong J
AD  - The Department of Pharmacology, Columbia University College of Physicians and 
      Surgeons, New York, New York.
FAU - Cao, Nancy
AU  - Cao N
AD  - University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
FAU - Wang, Yibin
AU  - Wang Y
AUID- ORCID: 0000-0003-0852-0767
AD  - Signature Research Program in Cardiovascular and Metabolic Diseases, Duke-NUS 
      Medical School, Singapore.
FAU - Steinberg, Susan F
AU  - Steinberg SF
AUID- ORCID: 0000-0002-2927-8570
AD  - The Department of Pharmacology, Columbia University College of Physicians and 
      Surgeons, New York, New York.
LA  - eng
SI  - figshare/10.6084/m9.figshare.20492826
GR  - R00 HL141626/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220916
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Amino Acids)
RN  - 0 (Lipids)
RN  - 0 (Protein Isoforms)
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.11.13 (PRKCA protein, human)
RN  - EC 2.7.11.13 (Prkca protein, mouse)
RN  - EC 2.7.11.13 (Protein Kinase C-alpha)
SB  - IM
MH  - Adult
MH  - Alternative Splicing
MH  - Amino Acids/genetics/metabolism
MH  - Animals
MH  - Humans
MH  - Lipids
MH  - Mice
MH  - Muscle, Skeletal/metabolism
MH  - Myocytes, Cardiac/metabolism
MH  - Protein Isoforms/genetics/metabolism
MH  - *Protein Kinase C-alpha/genetics/metabolism
MH  - *Proteomics
MH  - RNA, Messenger/metabolism
PMC - PMC9550568
OTO - NOTNLM
OT  - alternative splicing
OT  - growth signaling
OT  - lipid-dependent activation
OT  - protein kinase c
OT  - protein synthesis
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2022/09/17 06:00
MHDA- 2022/10/07 06:00
PMCR- 2023/10/01
CRDT- 2022/09/16 12:42
PHST- 2022/09/17 06:00 [pubmed]
PHST- 2022/10/07 06:00 [medline]
PHST- 2022/09/16 12:42 [entrez]
PHST- 2023/10/01 00:00 [pmc-release]
AID - H-00304-2022 [pii]
AID - 10.1152/ajpheart.00304.2022 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2022 Oct 1;323(4):H825-H832. doi: 
      10.1152/ajpheart.00304.2022. Epub 2022 Sep 16.