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Upstream regulation of the Hippo-Yap pathway in cardiomyocyte regeneration. Semin Cell Dev Biol 2020 04;100:11-19

Date

10/14/2019

Pubmed ID

31606277

Pubmed Central ID

PMC7263368

DOI

10.1016/j.semcdb.2019.09.004

Scopus ID

2-s2.0-85073003673   5 Citations

Abstract

The response of the adult mammalian heart to injury such as myocardial infarction has long been described as primarily fibrotic scarring and adverse remodeling with little to no regeneration of cardiomyocytes. Emerging studies have challenged this paradigm by demonstrating that, indeed, adult mammalian cardiomyocytes are capable of completing cytokinesis albeit at levels vastly insufficient to compensate for the loss of functional cardiomyocytes following ischemic injury. Thus, there is great interest in identifying mechanisms to guide adult cardiomyocyte cell cycle re-entry and facilitate endogenous heart regeneration. The Hippo signaling pathway is a core kinase cascade that functions to suppress the transcriptional co-activators Yap and Taz by phosphorylation and therefore cytoplasmic retention or phospho-degradation. This pathway has recently sparked interest in the field of cardiac regeneration as inhibition of Hippo kinase signaling or overdriving the transcriptional co-activator, Yap, significantly promotes proliferation of terminally differentiated adult mammalian cardiomyocytes and can restore function in failing mouse hearts. Thus, the Hippo pathway is an attractive therapeutic target for promoting cardiomyocyte renewal and cardiac regeneration. Although the core kinases and transcriptional activators of the Hippo pathway have been studied extensively over the last twenty years, the regulatory inputs of this pathway, particularly in vertebrates, are poorly understood. Recent studies have elucidated several upstream regulatory inputs to the Hippo pathway in adult mammalian cardiomyocytes that influence cell proliferation and heart regeneration. Considering upstream inputs to the Hippo pathway are thought to be context and cell type specific, targeting these various components could serve as a therapeutic approach for refining Hippo-Yap signaling in the heart. Here, we provide an overview of the emerging regulatory inputs to the Hippo pathway as they relate to mammalian cardiomyocytes and heart regeneration.

Author List

Flinn MA, Link BA, O'Meara CC

Authors

Brian A. Link PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Caitlin C. O'Meara PhD Assistant Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cell Cycle Proteins
Heart
Humans
Myocytes, Cardiac
Protein-Serine-Threonine Kinases
Regeneration
Transcription Factors
jenkins-FCD Prod-486 e3098984f26de787f5ecab75090d0a28e7f4f7c0