Hippo–YAP/TAZ signalling in organ regeneration and regenerative medicine

Abstract

The Hippo pathway and its downstream effectors, the transcriptional co-activators YAP and TAZ, regulate organ growth and cell plasticity during animal development and regeneration. Remarkably, experimental activation of YAP/TAZ in the mouse can promote regeneration in organs with poor or compromised regenerative capacity, such as the adult heart, and the liver and intestine of old or diseased mice. However, therapeutic YAP/TAZ activation may cause serious side effects. Most notably, YAP/TAZ are hyperactivated in human cancers and prolonged activation of YAP/TAZ triggers cancer development in mice. Thus, can the power of YAP/TAZ to promote regeneration be harnessed in a safe way? Here we review the role of Hippo signaling in animal regeneration, examine the promises and risks of YAP/TAZ activation for regenerative medicine, and discuss strategies to activate YAP/TAZ for regenerative therapy while minimizing adverse side effects. D. melanogaster Hpo kinase), the large tumor suppressor kinases 1 and 2 (LATS1 and LATS2, Warts in D. melanogaster), the adaptor proteins Salvador1, MOB1A/B (SAV1 and Mats in D. melanogaster), the homologous transcriptional co-activators YAP and TAZ (Yorkie in D. melanogaster), and the TEAD transcription factors (TEAD 1-4, Scalloped in D. melanogaster) (Fig.1) 9,12,39,40. Mechanistically, YAP/TAZ in complex with a TEAD transcription factor bind to gene enhancers, interact with chromatin remodelling factors, and modulate RNA Polymerase II (Pol II) to drive or repress the expression of target genes, which prominently include cell cycle, cell migration and cell fate regulators (see also below) 40-48. Of note, although TEAD transcription factors are required for YAP/TAZ target gene expression, YAP-TEAD complexes alone may not be sufficient to activate the different genetic programs. Indeed, bioinformatics analyses of the regulatory regions that are bound by YAP/TAZ-TEAD complexes identified cooperation between YAP/TEAD and other transcription factors 45,49-52 (Fig. 1). In addition, although TEAD factors are their main interaction partners, YAP/TAZ can interact with other DNA binding transcription factors such as p73 53 , RUNX 54 , and TBX5 55,56. Therefore, YAP/TAZ cooperate with various transcription factors to regulate target gene expression. Activation of MST1/2 induces the phosphorylation of SAV1 and MOB1A/B 57,58 , which assist MST1/2 in the recruitment, phosphorylation, and activation of LATS1/2 58-60. LATS1/2 can also be phosphorylated and activated by the MAP4K1-7 family kinases 61-63. Subsequently, LATS1/2 phosphorylate YAP and TAZ 32,39,40,46,64-66. YAP/TAZ phosphorylation by LATS1/2 causes their cytoplasmic sequestration by 14-3-3 proteins and triggers further phosphorylation by Casein kinase 1δ/ε as well as ubiquitylation by the SCF E3 ubiquitin ligase complex and proteasomal degradation 67-70. Thus, the core Hippo kinases inhibit YAP/TAZ activity and suppress the transcriptional output of the Hippo pathway.

Turning regenerative technologies into treatment to repair myocardial injuries

“…Unfortunately, the strategies that aim to induce endogenous myocyte turnover, although promising, do not guarantee that the resulting contractile cells will be able to counteract heart failure in humans or that a cell neoplastic transformation will not occur. In particular, activation of YAP, the major effector of the Hippo pathway, promotes proliferation and regeneration of cardiomyocytes after myocardial infarction, but it can bear notable risks in promoting cancer . In addition, the induction of cardiomyocyte turnover alone could not be sufficient to repair the complex myocardial architecture.…”

“…In particular, activation of YAP, the major effector of the Hippo pathway, promotes proliferation and regeneration of cardiomyocytes after myocardial infarction, 60 but it can bear notable risks in promoting cancer. 58…”

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

“…Regeneration occurs either by activation and amplification of resident stem cells, as in the epithelia of the skin and intestine, or through cellular de-differentiation and proliferation, as in the liver. In other instances, such as central nervous and cardiac-muscle tissues, cells exhibit little or no potential for regeneration after injury 1,4,5 .…”

Decoding WW Domain Tandem-mediated Target Recognitions in Tissue Growth and Cell Polarity

“…However, it is not clear how such large array of WW/PY-motif interactions in the Hippo-related signaling pathway are inter-related during cell growth processes and whether all these reported interactions occur in living cells. Since whether YAP is in nuclei or in cytoplasm dictates the fate of cell growth and polarity (Sun and Irvine, 2016, Moya and Halder, 2018, Fulford et al, 2018, Yu et al, 2015a, it is envisaged that at least some of the WW/PY-motif interactions need to be specific.…”

“…In cell growth and polarity regulations, YAP sits at the final converging point integrating both Hippo pathway-dependent and -independent upstream signals and regulating gene transcriptions via its WW tandem-mediated binding to PY-motif containing proteins including LATS, AMOTs and PTPN14 (Sun and Irvine, 2016, Moya and Halder, 2018, Fulford et al, 2018, Yu et al, 2015a. KIBRA also contains a WW tandem that binds to PY-motifs from the same set of proteins.…”