Document Detail


Basis for MAP4 dephosphorylation-related microtubule network densification in pressure overload cardiac hypertrophy.
MedLine Citation:
PMID:  20889984     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Increased activity of Ser/Thr protein phosphatases types 1 (PP1) and 2A (PP2A) during maladaptive cardiac hypertrophy contributes to cardiac dysfunction and eventual failure, partly through effects on calcium metabolism. A second maladaptive feature of pressure overload cardiac hypertrophy that instead leads to heart failure by interfering with cardiac contraction and intracellular transport is a dense microtubule network stabilized by decoration with microtubule-associated protein 4 (MAP4). In an earlier study we showed that the major determinant of MAP4-microtubule affinity, and thus microtubule network density and stability, is site-specific MAP4 dephosphorylation at Ser-924 and to a lesser extent at Ser-1056; this was found to be prominent in hypertrophied myocardium. Therefore, in seeking the etiology of this MAP4 dephosphorylation, we looked here at PP2A and PP1, as well as the upstream p21-activated kinase 1, in maladaptive pressure overload cardiac hypertrophy. The activity of each was increased persistently during maladaptive hypertrophy, and overexpression of PP2A or PP1 in normal hearts reproduced both the microtubule network phenotype and the dephosphorylation of MAP4 Ser-924 and Ser-1056 seen in hypertrophy. Given the major microtubule-based abnormalities of contractile and transport function in maladaptive hypertrophy, these findings constitute a second important mechanism for phosphatase-dependent pathology in the hypertrophied and failing heart.
Authors:
Guangmao Cheng; Masaru Takahashi; Anandakumar Shunmugavel; J Grace Wallenborn; Anna A DePaoli-Roach; Ulrich Gergs; Joachim Neumann; Dhandapani Kuppuswamy; Donald R Menick; George Cooper
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-10-02
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-11-29     Completed Date:  2010-12-30     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  38125-40     Citation Subset:  IM    
Affiliation:
Gazes Cardiac Research Institute, Cardiology Division, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29403, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cardiomegaly / genetics,  metabolism*
Cats
Heart Failure / genetics,  metabolism*
Mice
Mice, Transgenic
Microtubule-Associated Proteins / genetics,  metabolism*
Microtubules / genetics,  metabolism*
Myocardial Contraction / genetics
Phosphorylation / genetics
Protein Phosphatase 2 / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
HL094545/HL/NHLBI NIH HHS; HL104287/HL/NHLBI NIH HHS; HL48788/HL/NHLBI NIH HHS; R01 HL094545/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/MAP4; 0/Microtubule-Associated Proteins; EC 3.1.3.16/Protein Phosphatase 2
Comments/Corrections

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