Mechanism of IRSp53 inhibition and combinatorial activation by Cdc42 and downstream effectors

Kast, David J.; Yang, Chao; Disanza, Andrea; Boczkowska, Małgorzata; Madasu, Yadaiah; Scita, Giorgio; Svitkina, Tatyana; Domínguez, Roberto

doi:10.1038/nsmb.2781

Cited by 74 publications

(118 citation statements)

References 64 publications

(112 reference statements)

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“…While the nature of MIM activation is unknown, IRSp53, a MIM-related molecule, has a closed inactive conformation resulting from an intramolecular interaction (Kast et al, 2014), which can then be activated upon binding to Cdc42 (Disanza et al, 2013). However, the mutant MIM-I-BAR, like full-length MIM, also shows SDF-1-dependent binding to Rab7.…”

Section: Discussionmentioning

confidence: 99%

Missing-in-metastasis protein downregulates CXCR4 by promoting ubiquitylation and interaction with small Rab GTPases

Baxter

et al. 2017

Journal of Cell Science

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Surface expression of chemokine receptor CXCR4 is downregulated by missing-in-metastasis protein (MIM; also known as MTSS1), a member of the inverse BAR (I-BAR)-domain protein family that recognizes and generates membranes with negative curvature. Yet, the mechanism for the regulation is unknown. Here, we show that MIM forms a complex with CXCR4 by binding to E3 ubiquitin ligase AIP4 (also known as ITCH) in response to stromal cell-derived factor 1 (SDF-1; also known as CXCL12). Overexpression of MIM promoted CXCR4 ubiquitylation, inhibited cellular response to SDF-1, caused accumulation and aggregation of multivesicular bodies (MVBs) in the cytoplasm, and promoted CXCR4 sorting into MVBs in a manner depending on binding to AIP4. In response to SDF-1, MIM also bound transiently to the small GTPase Rab5 at 5 min and to Rab7 at 30 min. Binding to Rab7 requires an N-terminal coiled-coil motif, deletion of which abolished MIM-mediated MVB formation and CXCR4 internalization. Our results unveil a previously unknown property of MIM that establishes the linkage of protein ubiquitylation with Rab-guided trafficking of CXCR4 in endocytic vesicles.

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Section: Discussionmentioning

confidence: 99%

Missing-in-metastasis protein downregulates CXCR4 by promoting ubiquitylation and interaction with small Rab GTPases

Baxter

et al. 2017

Journal of Cell Science

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“…An increase in cytoneme length leads to a severe anterior shift of the midbrain-hindbrain boundary and causes a reduction of the forebrain that is comparable to that observed when Wnt proteins are ubiquitously overexpressed. IRSp53 regulates Cdc42 activity exclusively during the formation of filopodia (Kast et al, 2014). Concordantly, overexpression of the mutated IRSp53 4K blocked Cdc42 activity, resulting in shortening Wnt-positive cytonemes.…”

Section: Impact Of a Cytoneme-mediated Transport On The Wnt Morphogenmentioning

confidence: 99%

Role of cytonemes in Wnt transport

Stanganello

Scholpp

2016

Journal of Cell Science

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Wnt signaling regulates a broad variety of processes during embryonic development and disease. A hallmark of the Wnt signaling pathway is the formation of concentration gradients by Wnt proteins across responsive tissues, which determines cell fate in invertebrates and vertebrates. To fulfill its paracrine function, trafficking of the Wnt morphogen from an origin cell to a recipient cell must be tightly regulated. A variety of models have been proposed to explain the extracellular transport of these lipid-modified signaling proteins in the aqueous extracellular space; however, there is still considerable debate with regard to which mechanisms allow the precise distribution of ligand in order to generate a morphogenetic gradient within growing tissue. Recent evidence suggests that Wnt proteins are distributed along signaling filopodia during vertebrate and invertebrate embryogenesis. Cytoneme-mediated transport has profound impact on our understanding of how Wnt signaling propagates through tissues and allows the formation of a precise ligand distribution in the recipient tissue during embryonic growth. In this Commentary, we review extracellular trafficking mechanisms for Wnt proteins and discuss the growing evidence of cytoneme-based Wnt distribution in development and stem cell biology. We will also discuss their implication for Wnt signaling in the formation of the Wnt morphogenetic gradient during tissue patterning.

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“…2d). Next, we analysed the localization of the ubiquitously expressed multidomain scaffold protein IRSp53, which binds active Cdc42 and N-Wasp to promote filopodia formation 31,32 and found it in similar microdomains on the filopodium (Fig. 2e).…”

Section: Cell Extensions Carry Wnt Protein To Neighbouring Cellsmentioning

confidence: 99%

Filopodia-based Wnt transport during vertebrate tissue patterning

et al. 2015

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Paracrine Wnt/b-catenin signalling is important during developmental processes, tissue regeneration and stem cell regulation. Wnt proteins are morphogens, which form concentration gradients across responsive tissues. Little is known about the transport mechanism for these lipid-modified signalling proteins in vertebrates. Here we show that Wnt8a is transported on actin-based filopodia to contact responding cells and activate signalling during neural plate formation in zebrafish. Cdc42/N-Wasp regulates the formation of these Wnt-positive filopodia. Enhanced formation of filopodia increases the effective signalling range of Wnt by facilitating spreading. Consistently, reduction in filopodia leads to a restricted distribution of the ligand and a limited signalling range. Using a simulation, we provide evidence that such a short-range transport system for Wnt has a long-range signalling function. Indeed, we show that a filopodia-based transport system for Wnt8a controls anteroposterior patterning of the neural plate during vertebrate gastrulation.

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Mechanism of IRSp53 inhibition and combinatorial activation by Cdc42 and downstream effectors

Cited by 74 publications

References 64 publications

Missing-in-metastasis protein downregulates CXCR4 by promoting ubiquitylation and interaction with small Rab GTPases

Missing-in-metastasis protein downregulates CXCR4 by promoting ubiquitylation and interaction with small Rab GTPases

Role of cytonemes in Wnt transport

Filopodia-based Wnt transport during vertebrate tissue patterning

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