The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal

Abstract

Precise control of organ size is crucial during animal development and regeneration. In Drosophila and mammals, studies over the past decade have uncovered a critical role for the Hippo tumour-suppressor pathway in the regulation of organ size. Dysregulation of this pathway leads to massive overgrowth of tissue. The Hippo signalling pathway is highly conserved and limits organ size by phosphorylating and inhibiting the transcription co-activators YAP and TAZ in mammals and Yki in Drosophila, key regulators of proliferation and apoptosis. The Hippo pathway also has a critical role in the self-renewal and expansion of stem cells and tissue-specific progenitor cells, and has important functions in tissue regeneration. Emerging evidence shows that the Hippo pathway is regulated by cell polarity, cell adhesion and cell junction proteins. In this review we summarize current understanding of the composition and regulation of the Hippo pathway, and discuss how cell polarity and cell adhesion proteins inform the role of this pathway in organ size control and regeneration.

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

“…2). A large effort has been invested in elucidating the roles of Hippo signalling in human disease, establishing mammalian Hippo signalling as a novel tumour suppressor pathway that is essential for the regulation of tissue growth [27][28][29][30][31]. Unfortunately, these focused approaches also meant that possible mitotic functions were neglected to a certain extent.…”

“…Loss of Hippo, Mats or Warts could be functionally compensated by their mammalian counterparts MST2, LATS1 and MOB1A, respectively [24][25][26], strongly suggesting that, similar to the MEN/SIN, Hippo signalling is very highly conserved from flies to humans. Over the past years a series of studies using human cells and transgenic mice established that the core components of mammalian Hippo signalling represent tumour suppressor proteins [27][28][29][30][31]. However, in spite of the strong conservation of MEN/SIN and Hippo components, the involvement of the Hippo core cassette in mitotic exit in higher eukaryotes is not yet fully understood.…”

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

“…Yes-associated protein (YAP) is a transcriptional co-activator that plays key roles in the contact inhibition of cell growth and organ size restriction 15 . Cytoplasmic localization of YAP is promoted through its phosphorylation by the Hippo kinase cascade, whose components and function are well conserved in mammals.…”

Hippo signaling: to die or not to die

“…Hippo signaling thus acts through this pathway to suppress tumorigenesis. [2][3][4] DDR is a complex signaling process that maintains the integrity of the genome in response to DNA damage. 5,6 This signaling process involves a number of factors that either arrest the cell cycle and facilitate DNA repair or, if the DNA damage is too extensive to be repaired, induce apoptosis.…”

“…The mammalian Hippo tumor suppressor pathway has pivotal roles in regulating organ size, stem cell pluripotency and tumorigenesis. [2][3][4] The Hippo pathway is composed of a kinase cascade core that includes the MST1/2 serine/threonine kinase, the WW45 scaffold protein, MOB, and the serine/threonine LATS1/2 kinase. Activation of the core cascade through, for example, cell-cell contact due to high cell density leads to phosphorylation of the YAP and TAZ oncoproteins, leading to their sequestration in the cytoplasm and preventing their binding to TEAD transcription factors.…”