The Hippo signaling pathway in stem cell biology and cancer

Abstract

The Hippo signaling pathway, consisting of a highly conserved kinase cascade (MST and Lats) and downstream transcription coactivators (YAP and TAZ), plays a key role in tissue homeostasis and organ size control by regulating tissue-specific stem cells. Moreover, this pathway plays a prominent role in tissue repair and regeneration. Dysregulation of the Hippo pathway is associated with cancer development. Recent studies have revealed a complex network of upstream inputs, including cell density, mechanical sensation, and G-protein-coupled receptor (GPCR) signaling, that modulate Hippo pathway activity. This review focuses on the role of the Hippo pathway in stem cell biology and its potential implications in tissue homeostasis and cancer.

Keywords: Hippo pathway; YAP; cancer; regeneration; stem cell.

Figure 1. Schematic models of the Hippo pathway in Drosophila and mammals

Cells are shown with respective cellular junctions; adherens junction (AJ), tight junction (TJ), septate junction (SJ). Hippo pathway components in Drosophila and mammals are shown in various colors, with arrows and blunt lines indicating activation and inhibition, respectively. The yellow spheres indicate phosphorylation of target proteins by kinase. Continuous lines indicate known interactions, whereas dashed lines indicate unknown mechanisms. See introduction for further details.

Figure 2. A model of TE and ICM specification regulated by Hippo-YAP pathway in preimplantation embryo

During preimplantation, the outer blastomeres of the embryo form an outer epithelial trophectoderm (TE) that envelopes the remaining blastomeres, the inner cell mass (ICM). The Hippo pathway plays important roles in this cell fate specification. The outer cells have an outside exposed surface and are composed of plasma membranes with apical and basolateral domains, whereas inner cells are completely surrounded by outer cells. (A) In the outer cells, the nuclear localization of YAP and TEAD4 regulates specification of the TE lineage through activation of the TE-specific genes such as Gata3, Cdx2, and Eomes. (B) In the inner cells, cell–cell adhesions influence Hippo signaling. Activated Hippo pathway impairs YAP nuclear localization in the ICM lineage, thereby limiting TEAD4 transcription and abrogating expression of other TE-specific genes. Activation of Oct4 and Nanog maintains pluripotency and generates the ICM in mouse embryos. The yellow spheres indicate phosphorylation of target proteins by kinase.

Figure 3. Schematic illustration of Hippo pathway in liver

Endodermal progenitors generate hepatocytes and cholangiocytes that surround the bile duct system in adult liver. The Hering canal cells give rise to bipotential oval cells, which are capable of generating both hepatocytes and cholangiocytes. Hepatocyte regeneration is responsible for liver growth after partial hepatectomy. The exposure of the adult liver to hepatotoxins induces the proliferation of oval cell, but hepatocytes are slow to respond or do not respond at all to toxic injury. (A) In the hepatocytes, MST1/2 is activated by proteolytic cleavage that resulted in the loss of the Sav1 interacting SARAH domain. Cleaved MST1/2 is required to phosphorylate Mob1, but SAV1 is not required for Hippo pathway activity. This facilitates YAP phosphorylation, resulting in cytoplasmic retention by 14-3-3 binding and degradation by ubiquitin-proteasome-dependent manner. LATS1/2 activity is unaffected by MST1/2 inactivation in hepatocytes. But loss of NF2 decreases LATS1/2 and YAP phosphorylation, suggesting that the existence of unknown kinase other than MST1/2. Additionally, RASSF family proteins seem to have a role in MST1/2 regulation. LATS1/2 might indirectly inhibit YAP by activating unidentified kinase distinct from MST1/2. (B) In the oval cells, MST1/2-regulated phosphorylation on YAP Ser127 is unaffected by Sav1 inactivation. However, Sav1 regulates YAP protein level and localization via as yet defined mechanisms. There are no clear links between MST1/2 and LATS1/2 activation in oval cells. The mechanism underlying the inactivation of YAP inhibits oval cell proliferation. However, the role of oval cells in liver regeneration remains controversial.

Figure 4. The context-dependent role of YAP in intestinal stem cell expansion

In the intestinal stem cells (ISC), the Hippo pathway inhibits YAP activity by phosphorylation and cytosolic retention of YAP. The cytosolic YAP directly binds to β-catenin and subsequently inhibits the canonical Wnt signaling. In Mst1/2^−/− intestinal epithelia, loss of Hippo pathway regulation promotes dephosphorylation and nuclear translocation of YAP/β-catenin and induces their target gene expression. Activation of YAP/β-catenin results in the expansion of ISC. However, a controversial role of YAP has been demonstrated in the context of Wnt-induced intestinal regeneration. In YAP^−/− intestinal epithelia, hyperactivation of Wnt/β-catenin signaling results in ISC expansion, whereas YAP overexpression represses Wnt/β-catenin signaling, which leads to the loss of ISC and epithelial self-renewal. In this context, YAP functions to inhibit the nuclear translocation of disheveled (Dvl).