Scribble Acts in the Drosophila Fat-Hippo Pathway to Regulate Warts Activity

Abstract

Epithelial cells are the major cell-type for all organs in multicellular organisms. In order to achieve correct organ size, epithelial tissues need mechanisms that limit their proliferation, and protect tissues from damage caused by defective epithelial cells. Recently, the Hippo signaling pathway has emerged as a major mechanism that orchestrates epithelial development. Hippo signaling is required for cells to stop proliferation as in the absence of Hippo signaling tissues continue to proliferate and produce overgrown organs or tumors. Studies in Drosophila have led the way in providing a framework for how Hippo alters the pattern of gene transcription in target cells, leading to changes in cell proliferation, survival, and other behaviors. Scribble (Scrib) belongs to a class of neoplastic tumor suppressor genes that are required to establish apical-basal cell polarity. The disruption of apical-basal polarity leads to uncontrolled cell proliferation of epithelial cells. The interaction of apical basal polarity genes with the Hippo pathway has been an area of intense investigation. Loss of scrib has been known to affect Hippo pathway targets, however, its functions in the Hippo pathway still remain largely unknown. We investigated the interactions of Scrib with the Hippo pathway. We present data suggesting that Drosophila scrib acts downstream of the Fat (Ft) receptor, and requires Hippo signaling for its growth regulatory functions. We show that Ft requires Scrib to interact with Expanded (Ex) and Dachs (D), and for regulating Warts (Wts) levels and stability, thus placing Scrib in the Hippo pathway network.

Defining the Protein–Protein Interaction Network of the Human Hippo Pathway

“…It includes other proteins, such as Ajuba LIM protein, LIMD1 (33), and RASSF1 (36), that have also been characterized previously as regulators of these kinase complexes. Cluster 5 concentrated on the bait protein SCRIB, which has been shown to restrain TAZ's activities in breast cancer stem cells (43) and regulate Warts kinase activation in Drosophila (54). The clustered preys consisted mostly of other signaling pathway regulators, such as PAK1, PAK3, SHOC2, IRFBP1, IRFBP2, GIT1, and GIT2, which indicated that SCRIB functions as a scaffold protein, mediating the crosstalk between various signaling pathways and the Hippo pathway.…”

NOS1AP Functionally Associates with YAP To Regulate Hippo Signaling

“…Phosphorylation of YAP/TAZ on conserved serine residues restricts them to the cytosol, where they can associate with 14-3-3 proteins, be targeted for proteasomal degradation, or localize to regions of cell-cell contact, all of which prevent the nuclear localization and transcriptional activation of YAP/TAZ target genes (6). Recently, both genetic (7)(8)(9) and biochemical (9, 10) studies have revealed an association between the Hippo pathway and the polarity protein Scribble. Scribble is a large scaffolding protein that contains leucine-rich repeats (LRRs) at its N terminus and four PDZ domains that connect YAP/TAZ with MST1/2 and LATS1/2 (10), downstream of LKB1 and PAR-1 kinases (10).…”

Drosophila Casein Kinase 2 (CK2) Promotes Warts Protein to Suppress Yorkie Protein Activity for Growth Control

“…As a key player, Wts is regulated by several components in the Hpo pathway (10,55,56). Recently, it is reported that Merlin recruits Wts to the cell membrane where Wts is phosphorylated and activated by Hpo/Salvador (57).…”