Table 1.
Known mechanisms/interactions with other major pathways that impinge on Hippo signaling in somatic and embryonic stem cells
| Stem cell type | Phenotype | Mechanistic insight | Refs |
|---|---|---|---|
| Skin | α-catenin cKO or Yap O.E. causes epidermal SC expansion; leads to SCC | α-catenin recruits and indirectly binds YAP through 14-3-3 at adherens junctions (AJs) | 19, 55 |
| Liver | MST1/2 cKO or WW45/MER cKO expands hepatocytes and/or oval cells leading to mixed HCC/CC tumors. | Canonical Hippo signaling, with MST and WW45/MER controlling YAP localization in hepatocytes and oval cells and in oval cells only, respectively. | 26, 39, 41, 48–51 |
| Intestine | O.E. of active YAP or MST/SAV1 cKO expands progenitor-like cells and blocks differentiation | Active YAP promotes WNT signaling by enhancing β-catenin transcriptional activity and induces expression of Notch targets. | 41, 59, 60 |
| Cardiac muscle | WW45/LATS/MST cKO or YAP O.E. promotes cardiomyocyte proliferation. YAP cKO leads to myocardial hypoplasia. | Nuclear YAP binds β-catenin while indirectly stimulating WNT signaling through the IGF pathway. | 61, 62 |
| CNS | MST/LATS cKO or YAP activation expands neural progenitor cells in neural tube. YAP O.E. expands CGNPs in the cerebellum and leads to medulloblastoma. |
Canonical Hippo signaling in the neural tube. Shh induces expression and nuclear localization of YAP in cerebellar granule neural precursors (CGNPs). Notch induces YAP expression in the cortex. |
64–67 |
| ESCs | Loss of TAZ in hESCs and loss of YAP or TEAD in mESCs results in a loss of self-renewal. YAP O.E. prevents differentiation in mESCs |
In hESCs, TAZ promotes self-renewal by mediating TGF-β signals and controlling the localization of SMAD2/3-4. In mESCs, YAP binds SMAD1 in response to BMP signaling for ESC maintenance. |
73–77 |
Abbreviations: cKO: conditional knockout; SCC: squamous cell carcinoma; AJs: adherens junctions; HCC: hepatocellular carcinoma; CC: cholangiocarcinoma; O.E.: overexpression; IGF: insulin-like growth factor; Shh: sonic hedgehog; CGNP: cerebellar granule neural precursor; CSC: cancer stem cell; EMT: epithelial-mesenchymal transition; hESCs: human embryonic stem cells; mESCs: mouse embryonic stem cells; TGF-β: transforming growth factor β; BMP: bone morphogenic protein