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Review
. 2010 Oct-Dec;4(4):288-93.
doi: 10.4161/fly.4.4.13116. Epub 2010 Oct 21.

Lgl/aPKC and Crb regulate the Salvador/Warts/Hippo pathway

Linda M Parsons  1 , Nicola A Grzeschik, Melinda L Allott, Helena E Richardson
Affiliations
Review

Lgl/aPKC and Crb regulate the Salvador/Warts/Hippo pathway

Linda M Parsons et al. Fly (Austin). 2010 Oct-Dec.

Abstract

A key goal of developmental biology is to understand the mechanisms that coordinate organ growth. It has long been recognized that the genes that control apico-basal cell polarity also regulate tissue growth. How loss of cell polarity contributes to tissue overgrowth has been the subject of much speculation. Do loss-of-function mutations in cell polarity regulators result in secondary effects that globally deregulate cell proliferation, or do these genes specifically control growth pathways? Three recent papers have shown that the apico-basal polarity determinants Lgl/aPKC and Crb regulate tissue growth independently of their roles in cell polarity and coordinately regulate cell proliferation and cell death via the Salvador/Warts/Hippo (SWH) pathway. Lgl/aPKC are required for the correct localization of Hippo (Hpo)/Ras associated factor (RASSF), while Crb regulates the levels and localization of Expanded (Ex), indicating that cell polarity determinants modify SWH pathway activity by distinct mechanisms. Here, we review the key data that support these conclusions, highlight remaining questions and speculate on the underlying mechanisms by which the cell polarity complexes interact with the SWH pathway. Understanding the interactions between cell polarity regulators and the SWH pathway will improve our knowledge of how epithelial organization and tissue growth are coordinated during development and perturbed in disease states such as cancer.

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Figures

Figure 1
Figure 1
The JM domain of Crb is required for SWH pathway signaling. Images and overlay of en>crbJM and control en>UASGFP wings (A–C). Note that en>crbJM wings are larger than control wings indicating that the PBM is not required for tissue overgrowth. (D) Overexpression of a transgene that encodes a mutated JM domain (en>crbPBM) does not promote tissue overgrowth but induces polarity defects resulting in lost tissue. (E) Schematic representation of crb transgenes. Signal peptide (SP), transmembrane domain (TM), juxtamembrane FERM-binding motif (JM), PDZ-binding motif (PBM), and amino acid substitutions are indicated **(reviewed in refs. and 11).
Figure 2
Figure 2
Localization of Hpo is independent of kinase activity. Planar sections of larval eye discs. Posterior is to the left. GMRGal4 was crossed to UAS-hpo (A), UAS-hpoDN (B) and stained for Factin (Phallodin) and Hpo (α-Hpo). (A) Control GMR>hpo larval disc stained for Factin and Hpo. Hpo localization is cytoplasmic. (B) GMR>hpoDN larval disc stained for Factin and Hpo. Hpo localization is cytoplasmic and similar to control discs (A) suggesting that Hpo kinase activity is not required for localization.
Figure 3
Figure 3
(A) Lgl/aPKC regulates Yki activity by promoting the formation of Hpo/RASSF complexes. Lgl/aPKC regulate the SWH pathway by favoring the formation of inactive Hpo/Rassf over active Hpo/Sav protein complexes. Hpo/Rassf are unable to phophorylate Yki. Consequently, pYki levels are reduced and dephosphorylated Yki enters the nucleus to form a complex with Scalloped (Sd) and activate SWH pathway targets. Perhaps the mislocalization and formation of Hpo/Rassf complexes is due to disruptions in endocytosis. (B). Crb regulates Yki activity by reducing the levels of Ex/Yki complexes. Crb regulates the SWH pathway through direct interactions with Ex. Crb/Ex/Yki form a tripartite complex and Yki is sequestered in the cytoplasm and prevented from entering the nucleus by binding to Expanded (Ex). The overexpression of Crb reduces Ex/Yki complexes, freeing Yki to enter the nucleus, interact with Scalloped (Sd) and activate SWH target genes. It is possible that Ex/Yki complexes are regulated by ubiquitination and/or proteolysis. crb mutant tissue also shows overgrowth due to deregulation of Notch endocytosis but the influence of Notch signaling on SWH pathway targets remains to be determined.
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