Hippo Growth Control Pathway and Organ Size

Abstract

In multicellular organisms, regulation of growth control occurs because of the concerted action of multiple growth‐regulatory and patterning pathways. Among these, the Hippo (Hpo) pathway gained notoriety for its unique ability to simultaneously regulate cell proliferation and apoptosis to achieve the correct organ size. Initially discovered in Drosophila, this pathway is evolutionarily conserved, and acts as a universal regulator of organ size in metazoa. A complete pathway that integrates signals from the cell membrane to the nucleus has emerged, and multiple modes of Hpo pathway regulation have been elucidated. When the Hpo pathway is active, it acts as a brake on growth – cell proliferation is suppressed and apoptosis is promoted, whereas when the Hpo pathway is inactive, growth occurs – cell proliferation is promoted and apoptosis is suppressed. While the initial discovery of the pathway established its role in regulation of organ size and development, the focus has shifted considerably towards understanding its role in other biological processes such as maintaining tissue homeostasis, stem cell and tissue differentiation, cancer and regeneration. The Hpo signalling pathway functions in organ size control, and understanding its physiological functions will provide insights on its tissue‐ and cell‐type‐specific functions, and its involvement in diseases such as cancer.

Key Concepts

  • Cell proliferation and cell death must be regulated for balanced growth.
  • The regulation of Hippo pathway activity is key to regulating cell number to achieve the correct organ size and growth during normal development.
  • Hippo pathway activation promotes apoptosis and suppresses cell proliferation, whereas Hippo pathway inactivation promotes cell proliferation and suppresses apoptosis.
  • The Hippo pathway is a network of tumour suppressor genes, and genes regulating cell‐ and planar‐polarity.
  • Signalling interactions in the Hippo pathway ultimately converge on the regulation of the oncogene Yorkie pathway activity.
  • The Hippo pathway is conserved across species.
  • Hippo pathway is dysregulated in human cancer (e.g. loss of tumour suppressor gene neurofibromin 2 (NF2) is causal to schwannomas, and the YAP/TAZ oncoproteins are overexpressed in many human cancers [lung, breast, prostate and liver]).
  • Hippo pathway regulates stem cell renewal, regeneration and differentiation in a tissue‐ and context‐specific manner.

Keywords: Hippo pathway; Drosophila; tumour suppressor genes; oncogene; apoptosis; proliferation

Figure 1. The Drosophila Hippo pathway. Cartoon illustrating the signalling interactions among Hippo pathway genes is shown. Arrows indicate positive interactions, whereas inhibitory interactions are shown by a line.
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Further Reading

Chaulk SG, Lattanzi VJ, Hiemer SE, Fahlman RP and Varelas X (2014) The Hippo pathway effectors TAZ/YAP regulate dicer expression and microRNA biogenesis through Let‐7. Journal of Biological Chemistry 289: 1886–1891.

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Waghmare I, Roebke A, Minata M, Kango‐Singh M and Nakano I (2014) Intercellular cooperation and competition in brain cancers: lessons from Drosophila and human studies. Stem Cells Translational Medicine 3: 1262–1268.

Weiss EL (2013) Hippo unleashed! Proteome‐scale analysis reveals new views of Hippo pathway biology. Science Signaling 6: pe36.

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Waghmare, Indrayani, Verghese, Shilpi, and Kango‐Singh, Madhuri(May 2015) Hippo Growth Control Pathway and Organ Size. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026054]