Abstract
The Hippo signalling pathway and its central effector YAP regulate proliferation of cardiomyocytes and growth of the heart. Using genetic models in mice we show that the increased proliferation of embryonal and postnatal cardiomyocytes due to loss of the Hippo-signaling component SAV1 depends on the Myb-MuvB (MMB) complex. Similarly, proliferation of postnatal cardiomyocytes induced by constitutive active YAP requires MMB. Genome studies revealed that YAP and MMB regulate an overlapping set of cell cycle genes in cardiomyocytes. Protein-protein interaction studies in cell lines and with recombinant proteins showed that YAP binds directly to B-MYB, a subunit of MMB, in a manner dependent on the YAP WW domains and a PPXY motif in B-MYB. Disruption of the interaction by overexpression of the YAP binding domain of B-MYB strongly inhibits the proliferation of cardiomyocytes. Our results point to MMB as a critical downstream effector of YAP in the control of cardiomyocyte proliferation.
Highlights
The Hippo signaling pathway plays fundamental roles in proliferation and organ size control [1]
We identified a direct interaction between the B-MYB subunit of MMB and YAP
Based on the binding studies, we created a tool called MY-COMP that interferes with the association YAP to B-MYB and strongly inhibits proliferation of cardiomyocytes
Summary
The Hippo signaling pathway plays fundamental roles in proliferation and organ size control [1]. When the Hippo pathway is active, LATS1/2 phosphorylate the transcriptional coactivators YAP and TAZ, which results either in their cytoplasmic retention by 14-3-3 proteins or SCF-mediated proteasomal degradation [2]. Cardiac-specific deletion of the Hippo kinases LATS1/2 or of the scaffold protein SAV1 results in heart enlargement and increased proliferation of embryonal and postnatal cardiomyocytes due to increased YAP activity [7,8]. Recent studies report a better outcome after myocardial infarction in mice with hyperactivated YAP [8,10,11,12]. Together, these studies identify YAP as an important regulator of cardiomyocyte proliferation and cardiac regeneration. The detailed mechanisms by which YAP promotes cardiomyocyte proliferation are still unclear [13]
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