The Hippo pathway coordinates cell proliferation, apoptosis, and differentiation, and has emerged as a major regulator of organ development and regeneration. Central to the mammalian Hippo pathway is the action of the transcriptional regulators TAZ (also known as WWTR1) and YAP, which are controlled by a kinase cascade that is sensitive to mechanosensory and cell polarity cues.
Scope of review:
We review recent studies focused on the Hippo pathway in embryonic and somatic stem cell renewal and differentiation.
Accurate control of TAZ and YAP is crucial for the self-renewal of stem cells and in guiding distinct cell fate decisions. In vivo studies have implicated YAP as a key regulator of tissue-specific progenitor cell proliferation and tissue regeneration. Misappropriate activation of nuclear TAZ and YAP transcriptional activity drives tissue overgrowth and is implicated in cancer stem cell-like properties that promote tumor initiation.
Understanding the activity and regulation of Hippo pathway effectors will offer insight into human pathologies that evolve from the deregulation of stem cell populations. Given the roles of the Hippo pathway in directing cell fate and tissue regeneration, the discernment of Hippo pathway regulatory cues will be essential for the advancement of regenerative medicine. This article is part of a Special Issue entitled Biochemistry of Stem Cells.
"When activated by a developmental cue, the Hippo core Mst1/2 kinases activate the Lats1/2 kinases, which in turn phosphorylate and negatively regulate the transcriptional cofactor Yap. Control of Yap in this way modulates the transcription of many genes required for tissue-specific cell differentiation . "
[Show abstract][Hide abstract] ABSTRACT: The precise regulation of numbers and types of neurons through control of cell cycle exit and terminal differentiation is an essential aspect of neurogenesis. The Hippo signaling pathway has recently been identified as playing a crucial role in promoting cell cycle exit and terminal differentiation in multiple types of stem cells, including in retinal progenitor cells. When Hippo signaling is activated, the core Mst1/2 kinases activate the Lats1/2 kinases, which in turn phosphorylate and inhibit the transcriptional cofactor Yap. During mouse retinogenesis, overexpression of Yap prolongs progenitor cell proliferation, whereas inhibition of Yap decreases this proliferation and promotes retinal cell differentiation. However, to date, it remains unknown how the Hippo pathway affects the differentiation of distinct neuronal cell types such as photoreceptor cells. In this study, we investigated whether Hippo signaling regulates retinogenesis during early zebrafish development. Knockdown of zebrafish mst2 induced early embryonic defects, including altered retinal pigmentation and morphogenesis. Similar abnormal retinal phenotypes were observed in zebrafish embryos injected with a constitutively active form of yap [(yap (5SA)]. Loss of Yap's TEAD-binding domain, two WW domains, or transcription activation domain attenuated the retinal abnormalities induced by yap (5SA), indicating that all of these domains contribute to normal retinal development. Remarkably, yap (5SA)-expressing zebrafish embryos displayed decreased expression of transcription factors such as otx5 and crx, which orchestrate photoreceptor cell differentiation by activating the expression of rhodopsin and other photoreceptor cell genes. Co-immunoprecipitation experiments revealed that Rx1 is a novel interacting partner of Yap that regulates photoreceptor cell differentiation. Our results suggest that Yap suppresses the differentiation of photoreceptor cells from retinal progenitor cells by repressing Rx1-mediated transactivation of photoreceptor cell genes during zebrafish retinogenesis.
PLoS ONE 05/2014; 9(5):e97365. DOI:10.1371/journal.pone.0097365 · 3.23 Impact Factor
"Furthermore, recent work demonstrated a role of MST1/2 kinases as tumor suppressors because combined deficiency of MST1/2 kinases leads to loss of the inactivation of YAP phosphorylation, massive liver overgrowth, and development of HCC . Regarding liver cancer in human patients, the most compelling information related to YAP is that approximately 50% of human HCC show aberrant overexpression and nuclear localization of YAP  and a small fraction of which is attributable to YAP gene amplification . "
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the third leading cause of cancer mortality. Despite continuing development of new therapies, prognosis for patients with HCC remains extremely poor. In recent years, control of organ size becomes a hot topic in HCC development. The Hippo signaling pathway has been delineated and shown to be critical in controlling organ size in both Drosophila and mammals. The Hippo kinase cascade, a singling pathway that antagonizes the transcriptional coactivator Yes-associated protein (YAP), plays an important role in animal organ size control by regulating cell proliferation and apoptosis rates. During HCC development, this pathway is likely inactivated in tumor initiated cells that escape suppressive constrain exerted by the surrounding normal tissue, thus allowing clonal expansion and tumor development. We have reviewed evolutionary changes in YAP as well as other components of the Hippo pathway and described the relationships between YAP genes and HCC. We also discuss regulation of transcription factors that are up- and downstream of YAP in liver cancer development.
Gastroenterology Research and Practice 08/2013; 2013:187070. DOI:10.1155/2013/187070 · 1.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mesenchymal stem cells are pluripotent cells from bone marrow, which can be differentiated into the osteogenic, chondrogenic, and adipogenic lineages in vitro and are a source of cells in bone and cartilage tissue engineering. An improvement in current tissue-engineering protocols requires more detailed insight into the molecular cues that regulate the distinct steps of osteochondral differentiation. Because Wnt signaling has been widely implicated in mesenchymal differentiation, we analyzed the role of Wnt signaling in human mesenchymal stem cell (hMSC) biology by stimulation of the pathway with lithium chloride and Wnt3A-conditioned medium. We demonstrate a role for low levels of Wnt signaling in proliferation of uncommitted hMSCs and confirm that Wnt signaling controls osteoprogenitor proliferation. On the other hand, at high Wnt levels we observed a block in adipogenic differentiation and an increase in the expression of alkaline phosphatase, suggesting a role in the initiation of osteogenesis. The results of this study suggest that bone tissue engineering could benefit from the activation of critical levels of Wnt signaling at defined stages of differentiation. Moreover, our data suggest that hMSCs provide a valid in vitro model to study the role of Wnt signaling in mesenchymal biology.
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