One attractive strategy to improve outcome in heart failure

One attractive strategy to improve outcome in heart failure is to regenerate damaged myocardium by making more functional cardiomyocytes. Extensive work over the past two decades has overturned the prevailing dogma that adult cardiomyocytes do not undergo cell division by demonstrating that adult cardiomyocytes do proliferate, albeit at a low rate (Zhou et al., 2012). Several signaling pathways have been shown to regulate cardiomyocyte proliferation, such as IGF1 (Duerr et al., 1995), perisotin (Kuhn et al., 2007), neuregulin (Baliga et al., 1999; Bersell et al., 2009), and n-acetyl-l-cysteine growth factor (Engel et al., 2005). Recently, the newly defined Hippo/Yap pathway was found to play essential roles in the regulation of heart development and postnatal cardiomyocyte proliferation. In this review, we summarize recent advances in understanding the regulation of the Hippo/Yap signaling pathway, and the role of this pathway in the developing and adult heart. In addition, we discuss opportunities for therapeutic manipulation of Hippo/Yap signaling to enhance myocardial repair and regeneration.
How multicellular organisms establish and maintain proper organ size is a long-standing puzzle. Genetic screens in Drosophila for abnormal growth regulation phenotypes identified Merlin (Hamaratoglu et al., 2006), Warts (Xu et al., 1995), Hippo (Wu et al., 2003), Salvador (Tapon et al., 2002), Mats (Lai et al., 2005), and other mutants with similar phenotypes of tissue overgrowth, increased cell proliferation, and suppressed apoptosis. The shared phenotypes of these mutants suggested that the affected genes function in a common pathway that regulates organ growth. Further genetic and biochemical studies confirmed that these genes encode a kinase cascade, in which Merlin, a membrane-associated cytoskeletal scaffolding protein, genetically functions upstream of Hippo, a Ste-20 type kinase that phosphorylates and activates Warts. Salvador, a WW-repeat protein, serves as a scaffold to enhance Hippo activity (Wu et al., 2003), while Mats, a Mob superfamily protein, interacts with Warts to facilitate its kinase activity (Lai et al., 2005). The missing link between the Hippo kinase cascade and gene expression regulation was discovered by Duojia Pan\'s group in 2005 (Huang et al., 2005). A yeast two hybrid screen using Warts as the bait identified the transcriptional co-activator Yorkie as a Warts binding protein. Follow-up experiments showed that Yorkie promotes cell proliferation and tissue growth, that its transcriptional activity is negatively regulated by Hippo signaling, and that it is directly phosphorylated by Warts. Moreover, Yorkie inactivation blocked the tissue overgrowth phenotype of Hippo kinase cascade mutants, indicating that phosphorylation and inactivation of Yorkie is a major output of Hippo signaling. Yorkie is a transcriptional co-activator that lacks intrinsic DNA binding activity. The DNA binding transcription factor Scalloped was identified as a major Yorkie partner that is required for tissue overgrowth in Yorkie gain of function or Hippo pathway loss of function (Zhang et al., 2008; Wu et al., 2008; Zhao et al., 2008). Interestingly, over-expression of Yorkie but not Scalloped caused tissue overgrowth, suggesting that Yorkie, the protein modulated by Hippo signaling, is limiting for tissue growth rather than Scalloped (Wu et al., 2008).
Hippo/Yap signaling in mammals The Hippo/Yap signaling pathway is highly conserved between Drosophila and mammals. The mammalian orthologs of Drosophila Hippo, Salvador, Warts, Mats, Yorkie and Scalloped, are Mst1/2 (mammalian sterile twenty-like), Sav1 (Salvador-like homolog 1), Lats1/2 (large tumor suppressor), Mob1, Yap (YES-associated protein), and Tead1–4 (TEA domain family member), respectively. The presence of multiple isoforms of many of the mammalian orthologs has made their genetic analysis in mammals complicated. In the remainder of this review, we will use the mammal nomenclature to describe Hippo/Yap pathway components.