Mammalian Hippo pathway: from development to cancer and beyond

Abstract

The Hippo pathway was discovered as a signal transduction pathway that regulates organ size in Drosophila melanogaster. It is composed of three components: cell surface upstream regulators including cell adhesion molecules and cell polarity complexes; a kinase cascade comprising two serine-threonine kinases with regulators and adaptors; and a downstream target, a transcription coactivator. The coactivator mediates the transcription of cell proliferation-promoting and anti-apoptotic genes. The pathway negatively regulates the coactivator to restrict cell proliferation and to promote cell death. Thus, the pathway prevents tissue overgrowth and tumourigenesis. The framework of the pathway is conserved in mammals. A dysfunction of the pathway is frequently detected in human cancers and correlates with a poor prognosis. Recent works indicated that the Hippo pathway plays an important role in tissue homoeostasis through the regulation of stem cells, cell differentiation and tissue regeneration.

Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

“…Regulated by cell density, shape, and actin cytoskeleton, the mammalian Hippo pathway consists of a core kinase cascade in which Mst1 or Mst2 forms a complex with the adaptor protein WW45 and phosphorylates the LATS1/2 kinases and another adaptor protein MOB (32)(33)(34). The LATS/MOB complex subsequently phosphorylates YAP (at Ser127) and its paralog TAZ (at Ser89), leading to their cytoplasmic retention and repression (28,30,35). YAP protein level and activity are regulated at multiple levels by several additional regulators, including the FERM domain proteins Merlin/NF2 (neurofibromatosis 2) and FRMD6 and protein phosphatases PP2A and ASPP1 (28,30,35).…”

“…The LATS/MOB complex subsequently phosphorylates YAP (at Ser127) and its paralog TAZ (at Ser89), leading to their cytoplasmic retention and repression (28,30,35). YAP protein level and activity are regulated at multiple levels by several additional regulators, including the FERM domain proteins Merlin/NF2 (neurofibromatosis 2) and FRMD6 and protein phosphatases PP2A and ASPP1 (28,30,35). YAP can promote metastasis through interacting with the TEAD/ TEF transcription factors, and increased YAP/TEAD activity plays a causal role in cancer progression and metastasis (36).…”

MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1

“…We further identified a series of miR-135b target genes that functioned as tumour suppressors and belonged to a Hippo signalling pathway 28 . The mammalian Hippo pathway is mainly composed of a kinase cascade that includes MST1/2, LATS1/2, MOB1a/b and Sav1, which phosphorylates the transcriptional coactivator TAZ/YAP (refs 43, 44).…”

Systems Analysis of the NCI-60 Cancer Cell Lines by Alignment of Protein Pathway Activation Modules with “-OMIC” Data Fields and Therapeutic Response Signatures

“…On the basis of our analysis, we propose a model of interactions (Fig. 4) based on both previous data (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) and the interactions we found. This example provides evidence that our approach has identified "-omic" linkages that, although new, have basis in biochemical rationale and are supported, in part, by past research (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

“…In several pathway activation networks (IGF-1R, EGFR, AKT, mTOR, and apoptosis) we studied, we found a consistent linkage of MST1/MST2, PAK1/PAK2, LKB1, SGK1, and ABL phosphoproteins, RUNX1T1 gene methylation status, and miRNA-211. The MST protein family is known to be involved in the Hippo pathway, a signaling cascade that controls organ size through the regulation of cell proliferation and apoptosis (19,20). As many cancers are marked by unchecked cell division, Hippo family signaling has become increasingly significant in the study of human cancers; however, how this family integrates within the context of other biochemical events still remains unclear.…”