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Review
. 2019 Mar 4;218(3):742-756.
doi: 10.1083/jcb.201810103. Epub 2018 Dec 31.

Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation

Teresa T Bonello  1 , Mark Peifer  2   3   4
Affiliations
Review

Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation

Teresa T Bonello et al. J Cell Biol. .

Abstract

Key events ranging from cell polarity to proliferation regulation to neuronal signaling rely on the assembly of multiprotein adhesion or signaling complexes at particular subcellular sites. Multidomain scaffolding proteins nucleate assembly and direct localization of these complexes, and the protein Scribble and its relatives in the LAP protein family provide a paradigm for this. Scribble was originally identified because of its role in apical-basal polarity and epithelial integrity in Drosophila melanogaster It is now clear that Scribble acts to assemble and position diverse multiprotein complexes in processes ranging from planar polarity to adhesion to oriented cell division to synaptogenesis. Here, we explore what we have learned about the mechanisms of action of Scribble in the context of its multiple known interacting partners and discuss how this knowledge opens new questions about the full range of Scribble protein partners and their structural and signaling roles.

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Figures

Figure 1.
Figure 1.
Known Scribble-interacting proteins, mapped to the LRR, PDZ, or C-terminal region of Scribble. A plus sign (+) indicates a direct interaction with an individual PDZ domain, measured by peptide-phage display, yeast two-hybrid assay, binding assays using recombinantly expressed and purified GST-fusion proteins, or another biochemical strategy. No binding partners have been identified for the LAP-specific domains of Scribble. Proteins listed under coimmunoprecipitated with Scribble (inset box) have not been shown to directly interact with Scribble.
Figure 2.
Figure 2.
Contribution of Scribble domains to the subcellular localization and biological functions of Scribble. Gray bars indicate (1) regions sufficient for Scribble subcellular localization in different contexts (black text), (2) regions sufficient for particular biological functions (blue text), or (3) truncated versions that lack particular biological functions (red text). A broken line corresponds to a domain deletion. aC. elegans expresses LET-413, a member of the LAP protein family with only one PDZ domain. bIn addition to being restricted to the lateral membrane, Scribble colocalizes with β-catenin, indicating recruitment to adherens junctions. cA minimal Scribble construct containing the LRR domain and PDZ1 was required for effective membrane targeting. dData based on the circletail mouse mutant, a truncating mutation in Scribble that leads to the loss of PDZ3 and PDZ4.
Figure 3.
Figure 3.
Models for the roles of Scribble in organizing molecular interactomes involved in synaptogenesis, epithelial polarity, and adhesion, and growth regulation. (A) Cell adhesion molecules (Nrx/Nrg and N-Cad/β-Cat) are required for maintaining synaptic architecture and regulating neurotransmitter release. Both types of adhesion complexes interact with Scribble and β-PIX, facilitating localized Rac activity and F-actin polymerization. Polymerization of presynaptic actin is required for synaptic vesicle clustering and release from the active zone. Scribble also regulates trafficking of the NMDA receptor. (B) In the mature Drosophila ectoderm and imaginal disc epithelia Scribble localizes with Dlg and Lgl to the basolateral septate junctions. Scribble acts to antagonize aPKC and components of the adherens junction (AJ), excluding them from the basolateral domain. In turn, Scribble is antagonized by the apical polarity protein Crb. In cultured mammalian epithelial cells, Scribble regulates AJ and tight junction (TJ) organization, by stabilizing Ecad at the adherens junction via effects on p120 and via myosin stabilization mediated by DLC3. (C) Planar polarity, polarity across an epithelial sheet, is required for a number of processes, from sensory hair orientation to limb bud elongation. Core PCP proteins are asymmetrically localized and are conserved from Drosophila to mammals (vertebrate gene names in brackets). Vang and Fz localize to opposing sides of the cell, respectively, and form heterodimers between cells (Yang and Mlodzik, 2015). Scribble can physically interact with Vang as well as its vertebrate equivalent. Par3 is suggested to localize Vangl through an unknown mechanism. (D) Scribble interacts with several components of the Hippo signaling pathway, including the apical scaffold (Fat1) and the core kinase cassette (Mst1/2, Lats1/2). As a result, Scribble acts to restrain YAP and TAZ activity, transcriptional effectors of the Hippo cascade that control gene expression programs required for cell stemness, proliferation, survival, and EMT.
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