Ajuba LIM Proteins Are Negative Regulators of the Hippo Signaling Pathway

Abstract

Summary The mammalian Ajuba LIM proteins (Ajuba, LIMD1, WTIP) are cytosolic adapter proteins that exhibit the potential to communicate cell adhesive events with nuclear responses to remodel epithelia [1] [2]. Determining their role(s) in vivo, however, has been challenging due to overlapping tissue expression and functional redundancy. Thus, we turned to Drosophila where a single gene, CG11063 or djub, exists. Drosophila containing djub mutant loss-of-function alleles or depleted of dJub by RNAi identify djub as an essential gene for development and novel regulator of epithelial organ size as a component of the conserved Hippo pathway, which has been implicated in both tissue size control and cancer development [3-5] [6-9]. djub-deficient tissues were small, had decreased cell numbers as a result of increased apoptosis and decreased proliferation, due to downregulation of DIAP1 and cyclin E. This phenocopies tissues deficient for Yorkie (Yki), the downstream target of the Hippo pathway. djub genetically interacts with the Hippo pathway, and epistasis suggests that djub lies downstream of hpo. In mammalian and Drosophila cells, Ajuba LIM proteins/dJub interact with LATS/Wts and WW45/Sav to inhibit phosphorylation of YAP/Yki. This work describes a novel role for the Ajuba LIM proteins as negative regulators of the Hippo signaling pathway.

The Hippo Pathway Controls Border Cell Migration Through Distinct Mechanisms in Outer Border Cells and Polar Cells of the Drosophila Ovary

“…RNA interference (RNAi) lines obtained from the Bloomington Drosophila Stock Center or Vienna Drosophila Resource Center have been tested in previous studies (Das Thakur et al 2010;Genevet et al 2010;Boggiano et al 2011;Reddy and Irvine 2011;Chen and Verheyen 2012;Nagaraj et al 2012;Poernbacher et al 2012;Jukam et al 2013). slbo-Gal4-driven UAS-GFP flies were used as controls.…”

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…A LIM domain-containing protein Zyxin (Zyx) also inhibits Hippo signaling possibly by physical interaction with Wts and Dachs downstream of Fat (Rauskolb et al, 2011). dJub, another LIM domain-containing protein that physically interacts with Wts and Sav, was shown to negatively regulate Hippo signaling, although the detailed mechanism has not been delineated (Das Thakur et al, 2010). A number of cell polarity and cell adhesion proteins were also found to regulate the Hippo pathway.…”

Differential growth triggers mechanical feedback that elevates Hippo signaling

“…Yki activity is down-regulated through phosphorylation by the Warts (Wts) kinase, which promotes cytoplasmic localization of Yki. Wts is regulated in several ways, including phosphorylation by Hippo (7), regulation of Wts abundance (8), regulation of Wts localization (9,10), and regulation of Wts interaction with cofactors and inhibitors (11)(12)(13)(14)(15). We recently defined a mechanism for biomechanical regulation of Hippo signaling in which cytoskeletal tension induces recruitment of Ajuba LIM protein (Jub) to α-catenin, and thence recruitment of Wts to Jub (11).…”

“…We recently defined a mechanism for biomechanical regulation of Hippo signaling in which cytoskeletal tension induces recruitment of Ajuba LIM protein (Jub) to α-catenin, and thence recruitment of Wts to Jub (11). Jub is an inhibitor of Wts (12,13), and this tension-dependent corecruitment of Jub and Wts to adherens junctions is associated with reduced Wts activity, and hence increased Yki activity (11), at least in part because it prevents Wts from moving to sites where Wts gets activated (9). Conversely, under conditions of lower cytoskeletal tension, recruitment of Wts and Jub to adherens junctions is decreased, Wts activity is increased, and consequently Yki activity is decreased.…”