Double inhibition and activation mechanisms of Ephexin family RhoGEFs

Zhang, Meng; Lin, Lin; Wang, Chao; Zhu, Jinwei

doi:10.1073/pnas.2024465118

Cited by 6 publications

(12 citation statements)

References 47 publications

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“…This, together with our previous findings, suggests that the activity of RhoG, localized to the basolateral membrane by Scribble and Dlg1, is involved in the regulation of E-cadherin expression (Awadia et al, 2019). Based on these results and previous studies showing that SGEF may exist in an autoinhibited state, we believe its association with the complex may also function to release this autoinhibitory state to activate SGEF on site (Zhang et al, 2021).…”

Section: Discussionsupporting

confidence: 83%

The Scribble/SGEF/Dlg1 complex regulates the stability of apical junctions in epithelial cells

Rabino,

Awadia,

Ali

et al. 2024

Preprint

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SGEF, a RhoG specific GEF, can form a ternary complex with the Scribble polarity complex proteins Scribble and Dlg1, which regulates the formation and maintenance of adherens junctions and barrier function of epithelial cells. Notably, silencing SGEF results in a dramatic downregulation of the expression of both E-cadherin and ZO-1. However, the molecular mechanisms involved in the regulation of this pathway are not known. Here, we describe a novel signaling pathway governed by the Scribble/SGEF/Dlg1 complex. Our results show that an intact ternary complex is required to maintain the stability of the apical junctions, the expression of ZO-1, and TJ permeability. In contrast, only SGEF is necessary to regulate E-cadherin expression. The absence of SGEF destabilizes the E-cadherin/catenin complex at the membrane, triggering a positive feedback loop that exacerbates the phenotype through the repression of E-cadherin transcription in a process that involves the internalization of E-cadherin by endocytosis, β-catenin signaling and the transcriptional repressor Slug.

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Section: Discussionsupporting

confidence: 83%

The Scribble/SGEF/Dlg1 complex regulates the stability of apical junctions in epithelial cells

Rabino,

Awadia,

Ali

et al. 2024

Preprint

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“…Of particular interest, some of these partners are Rho GTPase regulatory proteins including GEFs and GTPase-activating proteins (GAPs). For example, SGEF and Ephexin4 are RhoG-specific GEFs ( 31 , 32 ), whereas ARHGAP21 and ARHGAP23 are RhoGAPs ( 33 ). Rho GTPases are master regulators of cytoskeletal dynamics and involved in cell motility and cell adhesion ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

“…S7). We previously demonstrated that PDZ domains of DLG1 (a close homolog of PSD-95) associate with and activate Ephexin4 RhoGEF to promote cell migration ( 32 ). A recent work reported that SGEF coordinates with DLG1 and Scribble to regulate the actomyosin-based contractility and barrier function at cell-cell junctions ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation-dependent recognition of diverse protein targets by the cryptic GK domain of MAGI MAGUKs

et al. 2023

Self Cite

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Dynamic signal transduction requires the rapid assembly and disassembly of signaling complexes, often mediated by phosphoprotein binding modules. The guanylate kinase-like (GK) domain of the membrane-associated guanylate kinases (MAGUKs) is such a module orchestrating signaling at cellular junctions. The MAGI subfamily of MAGUKs contains a truncated GK domain with unknown structure and function, although they participate in diverse physiological and pathological processes. Here, we demonstrate that the truncated GK domain of MAGI2 interacts with its adjacent PDZ0 domain to form a structural supramodule capable of recognizing phosphoproteins. A conserved phosphorylation-dependent binding motif for PDZ0-GK is delineated, which leads to identification of a set of previously unknown binding partners. We explore the structure and function of the MAGI2-target complex with an inhibitory peptide derived from the consensus motif. Our work reveals an action mechanism of the cryptic MAGI GKs and broadens our understanding of the target recognition rules of phosphoprotein binding modules.

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“…GEFs, on the other hand, activate GTPases by promoting the exchange of GDP for GTP. The proteins in the list are Rho-GEFs, as follows: SPATA13, ARHGEF4, ARHGEF26, NGEF, ARHGEF19, ARHGEF16, ARHGEF5, ARHGEF9, ARHGEF6, ARHGEF7 [ 120 , 123 , 124 , 125 , 126 ]. TRIO, KALRN, MCF2L, VAV1, VAV2, and VAV3 are multi-domain GEFs that regulate Rho family GTPases and other signaling pathways [ 120 , 127 , 128 ].…”

Section: Phylogenetic Classification Of Sh3dcpsmentioning

confidence: 99%

A Systematic Compilation of Human SH3 Domains: A Versatile Superfamily in Cellular Signaling

Mehrabipour

Jasemi

Dvorský

et al. 2023

Cells

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SRC homology 3 (SH3) domains are fundamental modules that enable the assembly of protein complexes through physical interactions with a pool of proline-rich/noncanonical motifs from partner proteins. They are widely studied modular building blocks across all five kingdoms of life and viruses, mediating various biological processes. The SH3 domains are also implicated in the development of human diseases, such as cancer, leukemia, osteoporosis, Alzheimer’s disease, and various infections. A database search of the human proteome reveals the existence of 298 SH3 domains in 221 SH3 domain-containing proteins (SH3DCPs), ranging from 13 to 720 kilodaltons. A phylogenetic analysis of human SH3DCPs based on their multi-domain architecture seems to be the most practical way to classify them functionally, with regard to various physiological pathways. This review further summarizes the achievements made in the classification of SH3 domain functions, their binding specificity, and their significance for various diseases when exploiting SH3 protein modular interactions as drug targets.

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Double inhibition and activation mechanisms of Ephexin family RhoGEFs

Cited by 6 publications

References 47 publications

The Scribble/SGEF/Dlg1 complex regulates the stability of apical junctions in epithelial cells

The Scribble/SGEF/Dlg1 complex regulates the stability of apical junctions in epithelial cells

Phosphorylation-dependent recognition of diverse protein targets by the cryptic GK domain of MAGI MAGUKs

A Systematic Compilation of Human SH3 Domains: A Versatile Superfamily in Cellular Signaling

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