Minimal Functional Domains of the Core Polarity Regulator Dlg

Overview

Journal Biol Open

Specialty Biology

Date 2022 Jun 20

PMID 35722710

Authors

Mark J Khoury

David Bilder

Affiliations

Soon will be listed here.

Abstract

The compartmentalized domains of polarized epithelial cells arise from mutually antagonistic actions between the apical Par complex and the basolateral Scrib module. In Drosophila, the Scrib module proteins Scribble (Scrib) and Discs-large (Dlg) are required to limit Lgl phosphorylation at the basolateral cortex, but how Scrib and Dlg could carry out such a 'protection' activity is not clear. We tested Protein Phosphatase 1α (PP1) as a potential mediator of this activity, but demonstrate that a significant component of Scrib and Dlg regulation of Lgl is PP1 independent, and found no evidence for a Scrib-Dlg-PP1 protein complex. However, the Dlg SH3 domain plays a role in Lgl protection and, in combination with the N-terminal region of the Dlg HOOK domain, in recruitment of Scrib to the membrane. We identify a 'minimal Dlg' comprised of the SH3 and HOOK domains that is both necessary and sufficient for Scrib localization and epithelial polarity function in vivo. This article has an associated First Person interview with the first author of the paper.

Citing Articles

A conditional strategy for cell-type-specific labeling of endogenous excitatory synapses in .

Parisi M, Aimino M, Mosca T Cell Rep Methods. 2023; 3(5):100477.

PMID: 37323572 PMC: 10261928. DOI: 10.1016/j.crmeth.2023.100477.

References

Lee T, Luo L . Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron. 1999; 22(3):451-61. DOI: 10.1016/s0896-6273(00)80701-1. View

Hutterer A, Betschinger J, Petronczki M, Knoblich J . Sequential roles of Cdc42, Par-6, aPKC, and Lgl in the establishment of epithelial polarity during Drosophila embryogenesis. Dev Cell. 2004; 6(6):845-54. DOI: 10.1016/j.devcel.2004.05.003. View

Troyanovsky R, Indra I, Kato R, Mitchell B, Troyanovsky S . Basolateral protein Scribble binds phosphatase PP1 to establish a signaling network maintaining apicobasal polarity. J Biol Chem. 2021; 297(5):101289. PMC: 8569552. DOI: 10.1016/j.jbc.2021.101289. View

Heroes E, Lesage B, Gornemann J, Beullens M, Meervelt L, Bollen M . The PP1 binding code: a molecular-lego strategy that governs specificity. FEBS J. 2012; 280(2):584-95. DOI: 10.1111/j.1742-4658.2012.08547.x. View

Goldstein B, Macara I . The PAR proteins: fundamental players in animal cell polarization. Dev Cell. 2007; 13(5):609-622. PMC: 2964935. DOI: 10.1016/j.devcel.2007.10.007. View

Wakula P, Beullens M, Ceulemans H, Stalmans W, Bollen M . Degeneracy and function of the ubiquitous RVXF motif that mediates binding to protein phosphatase-1. J Biol Chem. 2003; 278(21):18817-23. DOI: 10.1074/jbc.M300175200. View

Bellaiche Y, Radovic A, Woods D, Hough C, Parmentier M, OKane C . The Partner of Inscuteable/Discs-large complex is required to establish planar polarity during asymmetric cell division in Drosophila. Cell. 2001; 106(3):355-66. DOI: 10.1016/s0092-8674(01)00444-5. View

Bonello T, Choi W, Peifer M . Scribble and Discs-large direct initial assembly and positioning of adherens junctions during the establishment of apical-basal polarity. Development. 2019; 146(22). PMC: 6899021. DOI: 10.1242/dev.180976. View

de Vreede G, Morrison H, Houser A, Boileau R, Andersen D, Colombani J . A Drosophila Tumor Suppressor Gene Prevents Tonic TNF Signaling through Receptor N-Glycosylation. Dev Cell. 2018; 45(5):595-605.e4. PMC: 5995582. DOI: 10.1016/j.devcel.2018.05.012. View

10.

Khoury M, Bilder D . Distinct activities of Scrib module proteins organize epithelial polarity. Proc Natl Acad Sci U S A. 2020; 117(21):11531-11540. PMC: 7260944. DOI: 10.1073/pnas.1918462117. View

11.

Zhu J, Shang Y, Wan Q, Xia Y, Chen J, Du Q . Phosphorylation-dependent interaction between tumor suppressors Dlg and Lgl. Cell Res. 2014; 24(4):451-63. PMC: 3975498. DOI: 10.1038/cr.2014.16. View

12.

McGee A, Bredt D . Identification of an intramolecular interaction between the SH3 and guanylate kinase domains of PSD-95. J Biol Chem. 1999; 274(25):17431-6. DOI: 10.1074/jbc.274.25.17431. View

13.

Marcette J, Hood I, Johnston C, Doe C, Prehoda K . Allosteric control of regulated scaffolding in membrane-associated guanylate kinases. Biochemistry. 2009; 48(42):10014-9. PMC: 3535437. DOI: 10.1021/bi901160f. View

14.

Choi J, Troyanovsky R, Indra I, Mitchell B, Troyanovsky S . Scribble, Erbin, and Lano redundantly regulate epithelial polarity and apical adhesion complex. J Cell Biol. 2019; 218(7):2277-2293. PMC: 6605793. DOI: 10.1083/jcb.201804201. View

15.

St Johnston D, Ahringer J . Cell polarity in eggs and epithelia: parallels and diversity. Cell. 2010; 141(5):757-74. DOI: 10.1016/j.cell.2010.05.011. View

16.

Hendrickx A, Beullens M, Ceulemans H, Abt T, Van Eynde A, Nicolaescu E . Docking motif-guided mapping of the interactome of protein phosphatase-1. Chem Biol. 2009; 16(4):365-71. DOI: 10.1016/j.chembiol.2009.02.012. View

17.

Moreira S, Osswald M, Ventura G, Goncalves M, Sunkel C, Morais-de-Sa E . PP1-Mediated Dephosphorylation of Lgl Controls Apical-basal Polarity. Cell Rep. 2019; 26(2):293-301.e7. DOI: 10.1016/j.celrep.2018.12.060. View

18.

Yamanaka T, Horikoshi Y, Sugiyama Y, Ishiyama C, Suzuki A, Hirose T . Mammalian Lgl forms a protein complex with PAR-6 and aPKC independently of PAR-3 to regulate epithelial cell polarity. Curr Biol. 2003; 13(9):734-43. DOI: 10.1016/s0960-9822(03)00244-6. View

19.

Nakajima Y . Scrib module proteins: Control of epithelial architecture and planar spindle orientation. Int J Biochem Cell Biol. 2021; 136:106001. DOI: 10.1016/j.biocel.2021.106001. View

20.

Rademacher N, Kuropka B, Kunde S, Wahl M, Freund C, Shoichet S . Intramolecular domain dynamics regulate synaptic MAGUK protein interactions. Elife. 2019; 8. PMC: 6438691. DOI: 10.7554/eLife.41299. View