Modulation of the Hippo pathway and organ growth by RNA processing proteins

Abstract

The Hippo tumor-suppressor pathway regulates organ growth, cell proliferation, and stem cell biology. Defects in Hippo signaling and hyperactivation of its downstream effectors—Yorkie (Yki) in Drosophila and YAP/TAZ in mammals—result in progenitor cell expansion and overgrowth of multiple organs and contribute to cancer development. Deciphering the mechanisms that regulate the activity of the Hippo pathway is key to understanding its function and for therapeutic targeting. However, although the Hippo kinase cascade and several other upstream inputs have been identified, the mechanisms that regulate Yki/YAP/TAZ activity are still incompletely understood. To identify new regulators of Yki activity, we screened in Drosophila for suppressors of tissue overgrowth and Yki activation caused by overexpression of atypical protein kinase C (aPKC), a member of the apical cell polarity complex. In this screen, we identified mutations in the heterogeneous nuclear ribonucleoprotein Hrb27C that strongly suppressed the tissue defects induced by ectopic expression of aPKC. Hrb27C was required for aPKC-induced tissue growth and Yki target gene expression but did not affect general gene expression. Genetic and biochemical experiments showed that Hrb27C affects Yki phosphorylation. Other RNA-binding proteins known to interact with Hrb27C for mRNA transport in oocytes were also required for normal Yki activity, although they suppressed Yki output. Based on the known functions of Hrb27C, we conclude that Hrb27C-mediated control of mRNA splicing, localization, or translation is essential for coordinated activity of the Hippo pathway.

Effects of Spaceflight and Simulated Microgravity on YAP1 Expression in Cardiovascular Progenitors: Implications for Cell-Based Repair

“…Research in our own lab has shown that CPCs cultured on the ISS or on a clinostat are more proliferative and demonstrate elevated levels of transcripts encoding growth factors and DNA repair genes [4,13,17]. One of the most significant transcripts impacted by microgravity exposure of adult CPCs cultured on the ISS was yes-associated protein (YAP1), a key component of the Hippo signaling pathway, which regulates cell proliferation and is responsible for controlling organ growth [18,19,20,21]. YAP1 expression is well-documented as relevant for promoting cell survival and inhibiting apoptosis as well as promoting repair in regenerative studies [22,23].…”

Hippo pathway and Bonus control developmental cell fate decisions in the Drosophila eye

“…Su(var)2-10 belongs to the PIAS family of SUMO ligases and controls gene transcription and Drosophila eye specification (Betz et al, 2001; Hari et al, 2001; Ninova et al, 2020a; Ninova et al, 2020b). Hrb27C is an abundant Drosophila hnRNP that is involved in various aspects of post-transcriptional mRNA regulation and is implicated in the modulation of Yki activity (Goodrich et al, 2004; Mach et al, 2018). We tested whether these three Bon interactors are involved in the formation of Bon- and Yki-induced trichomes in adult eyes.…”

Rox8 promotes microRNA-dependent yki messenger RNA decay

“…RBPs have been reported to regulate transcription, mRNA procession, and translation, yet the role of RBPs in the Hippo pathway has remained largely elusive. A recent study found that Drosophila RBP Hrb27C regulates Yki phosphorylation indirectly via an unknown mechanism (55). In addition, two RBPs, Dnd1 and FUS, were shown to stabilize LATS mRNA in cultured hepatocellular carcinoma cells (56,57).…”