Document Detail


Site-specific microtubule-associated protein 4 dephosphorylation causes microtubule network densification in pressure overload cardiac hypertrophy.
MedLine Citation:
PMID:  20436166     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In severe pressure overload-induced cardiac hypertrophy, a dense, stabilized microtubule network forms that interferes with cardiocyte contraction and microtubule-based transport. This is associated with persistent transcriptional up-regulation of cardiac alpha- and beta-tubulin and microtubule-stabilizing microtubule-associated protein 4 (MAP4). There is also extensive microtubule decoration by MAP4, suggesting greater MAP4 affinity for microtubules. Because the major determinant of this affinity is site-specific MAP4 dephosphorylation, we characterized this in hypertrophied myocardium and then assessed the functional significance of each dephosphorylation site found by mimicking it in normal cardiocytes. We first isolated MAP4 from normal and pressure overload-hypertrophied feline myocardium; volume-overloaded myocardium, which has an equal degree and duration of hypertrophy but normal functional and cytoskeletal properties, served as a control for any nonspecific growth-related effects. After cloning cDNA-encoding feline MAP4 and obtaining its deduced amino acid sequence, we characterized by mass spectrometry any site-specific MAP4 dephosphorylation. Solely in pressure overload-hypertrophied myocardium, we identified striking MAP4 dephosphorylation at Ser-472 in the MAP4 N-terminal projection domain and at Ser-924 and Ser-1056 in the assembly-promoting region of the C-terminal microtubule-binding domain. Site-directed mutagenesis of MAP4 cDNA was then used to switch each serine to non-phosphorylatable alanine. Wild-type and mutated cDNAs were used to construct adenoviruses; microtubule network density, stability, and MAP4 decoration were assessed in normal cardiocytes following an equivalent level of MAP4 expression. The Ser-924 --> Ala MAP4 mutant produced a microtubule phenotype indistinguishable from that seen in pressure overload hypertrophy, such that Ser-924 MAP4 dephosphorylation during pressure overload hypertrophy may be central to this cytoskeletal abnormality.
Authors:
Panneerselvam Chinnakkannu; Venkatesababa Samanna; Guangmao Cheng; Zsolt Ablonczy; Catalin F Baicu; Jennifer R Bethard; Donald R Menick; Dhandapani Kuppuswamy; George Cooper
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-05-01
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-05     Completed Date:  2010-08-12     Revised Date:  2014-09-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  21837-48     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cardiomegaly / metabolism*
Cats
DNA, Complementary / metabolism
Mass Spectrometry / methods
Microscopy, Confocal / methods
Microtubule-Associated Proteins / metabolism*
Microtubules / metabolism*
Mutation
Myocardium / metabolism
Myocytes, Cardiac / cytology
Phosphorylation
Pressure
Protein Structure, Tertiary
Serine / chemistry
Grant Support
ID/Acronym/Agency:
HL094545/HL/NHLBI NIH HHS; HL104287/HL/NHLBI NIH HHS; HL48788/HL/NHLBI NIH HHS; R01 EY019065/EY/NEI NIH HHS; R01 HL094545/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Complementary; 0/MAP4; 0/Microtubule-Associated Proteins; 452VLY9402/Serine
Comments/Corrections

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