The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis.

By K. Harvey, Cathie M Pfleger, I. Hariharan. Cell, 2003

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Establishing and maintaining homeostasis is critical to the well-being of an organism and is determined by the balance of cell proliferation and death. Two genes that function together to regulate growth, proliferation, and apoptosis in Drosophila are warts (wts), encoding a serine/threonine kinase, and salvador (sav), encoding a WW domain containing Wts-interacting protein. However, the mechanisms by which sav and wts regulate growth and apoptosis are not well understood. Here, we describe mutations in hippo (hpo), which encodes a protein kinase most related to mammalian Mst1 and Mst2. Like wts and sav, hpo mutations result in increased tissue growth and impaired apoptosis characterized by elevated levels of the cell cycle regulator cyclin E and apoptosis inhibitor DIAP1. Hpo, Sav, and Wts interact physically and functionally, and regulate DIAP1 levels, likely by Hpo-mediated phosphorylation and subsequent degradation. Thus, Hpo links Sav and Wts to a key regulator of apoptosis.

Subfields: Cell Biology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/f162ae829ac84d2d793c15da0f8023340b8c0afa

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In Cell Biology

1. K. Guan
2. Bin Zhao
3. G. Halder
4. Duojia Pan
5. Fa-Xing Yu
6. S. Piccolo
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In Molecular Biology

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2. Bin Zhao
3. Duojia Pan
4. G. Halder
5. Fa-Xing Yu
6. Randy L. Johnson
7. S. Piccolo
8. M. Cordenonsi

In Oncology

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3. J. Avruch
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7. Erich A. Nigg
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Citations in the corpus

• The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals (2010, background): “…is a kinase cascade composed of four tumor suppressor proteins, including the Ste20-like kinase Hippo (Hpo) (Wu et al., 2003; Udan et al., 2003; Harvey et al., 2003; Pantalacci et al., 2003; Jia et al., 2003) and its regulatory protein Salvador (Sav) (Tapon et al., 2002; Kango-Singh et al.,…”
• Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. (2011, background): “…mutation of the Hippo pathway genes or transgenic expression of Yki, the YAP homolog, results in enlarged organ size (Kango-Singh et al. 2002; Tapon et al. 2002; Harvey et al. 2003; Jia et al. 2003; Pantalacci et al. 2003; Udan et al. 2003; Wu et al. 2003; Huang et al. 2005; Lai et al. 2005).”
• Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. (2005, background): “Cell overproliferation and apoptosis phenotypes caused by mats mutations are strikingly similar to those induced by loss-of-function mutations in hpo, sav, and wts genes, suggesting that mats may function in the Hpo-Sav-Wts pathway.”
• Mst1 and Mst2 maintain hepatocyte quiescence and suppress the development of hepatocellular carcinoma through inactivation of the Yap1 oncogene (2009, positive): “Loss of both Mst1 and Mst2 is sufficient to initiate hepatocyte proliferation, resulting in dramatic liver overgrowth, resistance to pro-apoptotic *Address correspondence to: Nabeel Bardeesy Ph.D., Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School,…”
• The biology of YAP/TAZ: hippo signaling and beyond. (2014, background): “In Drosophila, Yorkie is required for proliferation of several embryonic tissues, and loss of Hippo pathway components or F-actin inhibitors induces tissue overgrowth (57, 77, 81, 97, 129, 181, 201).”
• Hippo signaling in organ size control. (2007, background): “The next major advance in the genesis of the Hpo pathway was the identification of the Hpo tumor suppressor gene (Harvey et al. 2003; Jia et al. 2003; Pantalacci et al. 2003; Udan et al. 2003; Wu et al. 2003), which encodes a Ste-20 family protein kinase with a similar loss-of-function overgrowth…”
• Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. (2012, background): “…pathway that limits organ size under physiological conditions (Justice et al. 1995; Xu et al. 1995; Kango-Singh et al. 2002; Tapon et al. 2002; Harvey et al. 2003; Jia et al. 2003; Pantalacci et al. 2003; Udan et al. 2003; Wu et al. 2003; Huang et al. 2005; Lai et al. 2005; Dong et al. 2007).”
• The Hippo pathway: regulators and regulations. (2013, background): “Genetic inactivation of genes, including Warts (Wts) (Justice et al. 1995; Xu et al. 1995), Hippo (Hpo) (Harvey et al. 2003; Jia et al. 2003; Pantalacci et al. 2003; Udan et al. 2003; Wu et al. 2003), Salvador (Sav; also known as Shar-Pei) (KangoSingh et al. 2002; Tapon et al. 2002), and Mats (Lai…”
• Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. (2015, positive): “Several years later, a flurry of studies showed that Salvador (sav) (Kango-Singh et al., 2002; Tapon et al., 2002), Hippo (hpo) (Harvey et al., 2003; Jia et al., 2003; Pantalacci et al., 2003; Udan et al., 2003; Wu et al., 2003), and Mob as tumor suppressor (mats) (Lai et al., 2005) mutant…”
• Mechanisms of Hippo pathway regulation (2016, positive): “1B; Harvey et al. 2003; Jia et al. 2003; Pantalacci et al. 2003; Udan et al. 2003; Wu et al. 2003). hpo mutants exhibit uncontrolled growth in multiple tissues due to excessive cell proliferation and reduced apoptosis.”
• The Hippo Signaling Pathway in Development and Disease (2019, background): “, 2002), hippo (hpo) (Harvey et al., 2003; Jia et al., 2003; Pantalacci et al., 2003; Udan et al., 2003; Wu et al., 2003), and mob as tumor suppressor (mats) (Lai et al.”
• The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. (2008, background): “Loss-of-function mutations in the hpo pathway components including hpo, sav, and wts resulted in similar tissue overgrowth phenotypes (Harvey et al., 2003; Jia et al., 2003; Pantalacci et al., 2003; Tapon et al., 2002; Udan et al., 2003; Wu et al., 2003).”
• A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). (2010, background): “Regulation of YAP/ Yki activity was first revealed by genetic studies of the Hippo tumor suppressor pathway in Drosophila (KangoSingh et al. 2002; Tapon et al. 2002; Harvey et al. 2003; Jia et al. 2003; Pantalacci et al. 2003; Udan et al. 2003; S Wu et al. 2003; Lai et al. 2005).”