Actin dynamics are crucial for Hippo

Actin dynamics are crucial for Hippo signal transduction, as evidenced by the fact that inhibiting 3-Methyladenine manufacturer cytoskeleton dynamics initiated Hippo signaling in both Drosophila and mammalian cells (Dupont et al., 2011; Fernandez et al., 2011). Both actin polymerization inhibitor Latrunculin B and Rho GTPase inhibitor C3 promoted NF2 and Lats interaction (Yin et al., 2013) and increased Lats activity (Yu et al., 2012). How actin dynamics regulate Lats activity is an important gap in our understanding of Hippo signal transduction. Because the submembrane region near adherens junctions is enriched for both Hippo pathway components and actin cytoskeleton, this subcellular compartment is likely to be the arena in which actin dynamics modulate Lats.
Yap/TAZ regulation of cellular proliferation and organ size As the crucial link between the Hippo kinase cascade and gene transcription, Yap has been intensely studied since its identification as an effector of the Hippo pathway (Huang et al., 2005). Yap has 5 HXRXXS motifs that are potential Lats1/2 phosphorylation sites. Mutation of serine 127 to alanine (S127A) largely abolished Mst2/Lats2-induced Yap phosphorylation, 14-3-3 binding, and Yap nuclear export, indicating that Yap S127 is the major Lats1/2 phosphorylation site that regulates its nuclear/cytoplasmic distribution (Zhao et al., 2007). Yap S127 phosphorylation did not directly affect Yap and Tead interaction, but rather decreased the interaction between Yap and Tead due Yap cytoplasmic localization. In the liver, overexpression of activated Yap (Yap[S127A]) for one week doubled the liver size. This dramatic effect on organ size was due to increased proliferation and decreased apoptosis of liver cells (Dong et al., 2007; Camargo et al., 2007). In the cultured mammalian cells, Hippo/Yap signaling has been shown to be central to contact inhibition: cell–cell contacts activate Hippo to restrain Yap, thereby limiting cell proliferation. Yap overexpression overcomes contact inhibition in a Tead-dependent manner (Zhao et al., 2007). Yap promotes cell proliferation by stimulating the expression of Ccna2, Ccnb1, Cdc2, Aurka, Aurkb, and Cdc25b (von Gise et al., 2012). At the same time, Yap limits cellular apoptosis by stimulating expression of Birc5 and Birc2 (Dong et al., 2007). As a vital transcriptional regulator, Yap is a nodal point regulated by numerous upstream signaling pathways besides the canonical Hippo kinase cascade, including the YES/SRC tyrosine kinase pathway, the Wnt/β-catenin pathway, and the JNK pathway. Yap was first identified as a YES-associated protein (Sudol, 1994). In osteoblast cells, Yap directly interacts with RUNX2 to suppress its transcriptional activity. The phosphorylation of Yap by YES/SRC tyrosine kinase is required for Yap to interact with RUNX2, as blocking YES/SRC kinase activity abolished the interaction between these two proteins (Zaidi et al., 2004). In tumor cells, Wnt signaling regulates Yap expression both transcriptionally and post-transcriptionally: in colorectal carcinoma cells, the β-catenin/TCF4 complex directly regulated Yap expression (Konsavage et al., 2012), while in liver cancer cells the Wnt/β-catenin downstream target Tribbles homolog 2 (TRIB2) stabilized Yap by preventing its degradation (Wang et al., 2013). Conversely, Yap also regulates canonical Wnt signaling by direct interaction with β-catenin. This interaction modulates β-catenin/TCF transcriptional activity (Heallen et al., 2011) and β-catenin subcellular localization (Imajo et al., 2012). In a screen for kinases that directly phosphorylate Yap, Tomlinso et al. found that JNKs are robust Yap kinases (Tomlinson et al., 2010). This study showed that PKCα and ERK2 also phosphorylate Yap. These studies indicate that Yap is a key nodal point regulated by multiple signaling pathways.
Hippo/Yap pathway in the heart The fetal heart grows primarily by expansion of cardiomyocyte number (hyperplastic growth), while the postnatal heart grows mainly by enlargement of cardiomyocytes (hypertrophic growth). Studies of gain and loss of function mutations in Hippo/Yap pathway components in the heart (Table 1) have implicated this pathway in regulating both forms of heart growth.