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Lgl regulates the hippo pathway independently of Fat/Dachs, Kibra/Expanded/Merlin and dRASSF/dSTRIPAK

Parsons, L. M., Grzeschik, N. A. & Richardson, H. E., 1-Jun-2014, In : Cancers. 6, 2, p. 879-896 18 p.

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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. © 2014 by the authors; licensee MDPI, Basel, Switzerland.
Original languageEnglish
Pages (from-to)879-896
Number of pages18
JournalCancers
Volume6
Issue number2
Publication statusPublished - 1-Jun-2014

    Keywords

  • aPKC, Cell polarity, dRASSF, Drosophila, dSTRIPAK complex, Hpo, Lgl, Ras, Tumor suppressor, Dachs protein, Drosophila protein, Fat protein, Hippo protein, Kibra Expanded Merlin complex, mitogen activated protein kinase, protein kinase C, protein Lg1, Ras association factor, regulator protein, striatin interacting phophatase and kinase, unclassified drug, adult, animal tissue, article, cell death, cell polarity, controlled study, enzyme activation, enzyme activity, female, larval stage, male, molecular dynamics, nonhuman, phenotype, protein depletion, protein expression, protein function, protein localization, protein stability, pupation, RNA interference, upregulation

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