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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
Received: 6 May 2013; in revised form: 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 which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

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.

AMA Style

Parsons LM, Grzeschik NA, Richardson HE. lgl Regulates the Hippo Pathway Independently of Fat/Dachs, Kibra/Expanded/Merlin and dRASSF/dSTRIPAK. Cancers. 2014; 6(2):879-896.

Chicago/Turabian Style

Parsons, Linda M.; Grzeschik, Nicola A.; Richardson, Helena E. 2014. "lgl Regulates the Hippo Pathway Independently of Fat/Dachs, Kibra/Expanded/Merlin and dRASSF/dSTRIPAK." Cancers 6, no. 2: 879-896.



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