Waardenberg, Ashley J., Bernardo, Bianca C., Ng, Dominic C. H., Shepherd, Peter R., Cemerlang, Nelly, Sbroggiò, Mauro, Wells, Christine A., Dalrymple, Brian P., Brancaccio, Mara, Lin, Ruby C. Y., McMullen, Julie R., and UNSPECIFIED (2011) Phosphoinositide 3-Kinase (PI3K(p110α)) directly regulates key components of the Z-disc and cardiac structure. Journal of Biological Chemistry, 286 (35). pp. 30837-30846.

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Abstract

Maintenance of cardiac structure and Z-disc signaling are key factors responsible for protecting the heart in a setting of stress, but how these processes are regulated is not well defined. We recently demonstrated that PI3K(p110α) protects the heart against myocardial infarction. The aim of this study was to determine whether PI3K(p110α) directly regulates components of the Z-disc and cardiac structure. To address this question, a unique three-dimensional virtual muscle model was applied to gene expression data from transgenic mice with increased or decreased PI3K(p110α) activity under basal conditions (sham) and in a setting of myocardial infarction to display the location of structural proteins. Key findings from this analysis were then validated experimentally. The three-dimensional virtual muscle model visually highlighted reciprocally regulated transcripts associated with PI3K activation that encoded key components of the Z-disc and costamere, including melusin. Studies were performed to assess whether PI3K and melusin interact in the heart. Here, we identify a novel melusin-PI3K interaction that generates lipid kinase activity. The direct impact of PI3K(p110α) on myocyte structure was assessed by treating neonatal rat ventricular myocytes with PI3K(p110α) inhibitors and examining the myofiber morphology of hearts from PI3K transgenic mice. Results demonstrate that PI3K is critical for myofiber maturation and Z-disc alignment. In summary, PI3K regulates the expression of genes essential for cardiac structure and Z-disc signaling, interacts with melusin, and is critical for Z-disc alignment.

Item ID:	55663
Item Type:	Article (Research - C1)
ISSN:	1083-351X
Copyright Information:	Copyright © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
Additional Information:	Copyright: Manuscripts initially submitted prior to January 1, 2018 are subject to JBC’s former policy whereby, as a condition of publication, authors transfer copyright to ASBMB upon acceptance. Authors of manuscripts, submitted at any time, need not contact the journal to request permission to reuse their own material. Authors who granted ASBMB exclusive license to publish and authors who transferred copyright to ASBMB, are allowed to do the following: 4. to post the final edited PDFs, created by ASBMB, to their own departmental/university websites, provided that the posting does not happen until 12 months after publication of the work in the Journal of Biological Chemistry, and that a link to the article in the Journal of Biological Chemistry is included.
Funders:	National Health and Medical Research Council (NHMRC), Australian Research Council (ARC), CSIRO, Griffith University (GU), University of Melbourne (UM), University of New South Wales (UNSW), Victorian Government's Operational Infrastructure Support Program
Projects and Grants:	NHMRC Project Grant 367600, ARC Future Fellowship FT0001657, Honorary NHMRC Senior Research Fellowship 586604, NHMRC Peter Doherty Fellowship 351012, UM Roper fellowship, CSIRO Food Futures National Research Flagship, UNSW Vice Chancellor Research Fellowship
Date Deposited:	28 Sep 2018 05:37
FoR Codes:	06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060102 Bioinformatics @ 100%
SEO Codes:	97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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