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Cancers 2014, 6(2), 879-896; doi:10.3390/cancers6020879
Article

lgl Regulates the Hippo Pathway Independently of Fat/Dachs, Kibra/Expanded/Merlin and dRASSF/dSTRIPAK

1,2,†,* , 1,‡
 and
1,3,4,5
1 Cell Cycle and Development Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia 2 Department of Genetics, University of Melbourne, Melbourne, Victoria 3010, Australia 3 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria 3010, Australia 4 Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria 3010, Australia 5 Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria 3010, Australia Present address: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria 3010, Australia. Present address: Department of Cell Biology, University Medical Centre Groningen, Groningen, The Netherlands.
* Author to whom correspondence should be addressed.
Received: 6 May 2013 / Revised: 12 March 2014 / Accepted: 25 March 2014 / Published: 16 April 2014
(This article belongs to the Special Issue RASSF Signalling in Cancer)
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Abstract

In both Drosophila and mammalian systems, the Hippo (Hpo) signalling pathway controls tissue growth by inhibiting cell proliferation and promoting apoptosis. The core pathway consists of a protein kinase Hpo (MST1/2 in mammals) that is regulated by a number of upstream inputs including Drosophila Ras Association Factor, dRASSF. We have previously shown in the developing Drosophila eye epithelium that loss of the apico-basal cell polarity regulator lethal-(2)-giant-larvae (lgl), and the concomitant increase in aPKC activity, results in ectopic proliferation and suppression of developmental cell death by blocking Hpo pathway signalling. Here, we further explore how Lgl/aPKC interacts with the Hpo pathway. Deregulation of the Hpo pathway by Lgl depletion is associated with the mislocalization of Hpo and dRASSF. We demonstrate that Lgl/aPKC regulate the Hpo pathway independently of upstream inputs from Fat/Dachs and the Kibra/Expanded/Merlin complex. We show depletion of Lgl also results in accumulation and mislocalization of components of the dSTRIPAK complex, a major phosphatase complex that directly binds to dRASSF and represses Hpo activity. However, depleting dSTRIPAK components, or removal of dRASSF did not rescue the lgl/ or aPKC overexpression phenotypes. Thus, Lgl/aPKC regulate Hpo activity by a novel mechanism, independently of dRASSF and dSTRIPAK. Surprisingly, removal of dRASSF in tissue with increased aPKC activity results in mild tissue overgrowth, indicating that in this context dRASSF acts as a tumor suppressor. This effect was independent of the Hpo and Ras Mitogen Activated Protein Kinase (MAPK) pathways, suggesting that dRASSF regulates a novel pathway to control tissue growth.
Keywords: tumor suppressor; cell polarity; Drosophila; Lgl; aPKC; dRASSF; Hpo; Ras; dSTRIPAK complex tumor suppressor; cell polarity; Drosophila; Lgl; aPKC; dRASSF; Hpo; Ras; dSTRIPAK complex
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Parsons, L.M.; Grzeschik, N.A.; Richardson, H.E. lgl Regulates the Hippo Pathway Independently of Fat/Dachs, Kibra/Expanded/Merlin and dRASSF/dSTRIPAK. Cancers 2014, 6, 879-896.

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