title: lgl Regulates the Hippo Pathway Independently of Fat/Dachs, Kibra/Expanded/Merlin and dRASSF/dSTRIPAK.
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.
authors.affiliation: Cell Cycle and Development Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia. parsonsl@unimelb.edu.au.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Parsons
authors.affiliation: Cell Cycle and Development Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia. helena.richardson@petermac.org.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Grzeschik
authors.affiliation: Cell Cycle and Development Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia. n.a.grzeschik@umcg.nl.
authors.forename: Helena E
authors.initials: HE
authors.lastname: Richardson
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