CCM1–ICAP-1 complex controls β1 integrin–dependent endothelial contractility and fibronectin remodeling

Faurobert, Eva; Rome, Claire; Lisowska, Justyna; Manet-Dupé, Sandra; Boulday, Gwénola; Malbouyres, Marilyne; Balland, Martial; Bouin, Anne-Pascale; Kéramidas, Michelle; Bouvard, Daniel; Coll, Jean‐Luc; Ruggiero, Florence; Tournier‐Lasserve, Elisabeth; Albiges-Rizo, Corinne

doi:10.1083/jcb.201303044

Cited by 94 publications

(176 citation statements)

References 82 publications

(155 reference statements)

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“…ICAP-1 (also known as ITGB1BP1), a negative regulator of β1 integrin, enables the cell to sense ECM density to adapt its adhesive and migratory responses (Millon-Frémillon et al, 2008) and to control fibronectin (FN) remodeling (Brunner et al, 2011;Faurobert et al, 2013). ICAP-1 specifically binds to the cytoplasmic tail of β1 integrin, maintaining the integrin in its inactivated form by competing with the two activators named Kindlin and talin (Brunner et al, 2011;Millon-Frémillon et al, 2008;Montanez et al, 2008;Ye et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to its role in the β1 integrin activation cycle (MillonFrémillon et al, 2008), ICAP-1 interferes with small GTPase signaling and cell contractility by putting a cap on RhoA activation (Faurobert et al, 2013) and inhibiting Rac1 and Cdc42 (Degani et al, 2002). So far, how ICAP-1 can regulate both RhoA-ROCK signaling and the Cdc42 and Rac1 pathway was unclear.…”

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confidence: 99%

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ICAP-1 monoubiquitylation coordinates matrix density and rigidity sensing for cell migration through ROCK2–MRCKα balance

Bouin

Kyumurkov

Régent-Kloeckner

et al. 2017

Journal of Cell Science

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There was an error published in J. Cell Sci. 130, 626-636.The name of the author Alexander Kyumurkov was incorrect in the original author list. The correct spelling is given above.The authors apologise to the readers for any confusion that this error might have caused. 1195 ABSTRACTCell migration is a complex process requiring density and rigidity sensing of the microenvironment to adapt cell migratory speed through focal adhesion and actin cytoskeleton regulation. ICAP-1 (also known as ITGB1BP1), a β1 integrin partner, is essential for ensuring integrin activation cycle and focal adhesion formation. We show that ICAP-1 is monoubiquitylated by Smurf1, preventing ICAP-1 binding to β1 integrin. The non-ubiquitylatable form of ICAP-1 modifies β1 integrin focal adhesion organization and interferes with fibronectin density sensing. ICAP-1 is also required for adapting cell migration in response to substrate stiffness in a β1-integrin-independent manner. ICAP-1 monoubiquitylation regulates rigidity sensing by increasing MRCKα (also known as CDC42BPA)-dependent cell contractility through myosin phosphorylation independently of substrate rigidity. We provide evidence that ICAP-1 monoubiquitylation helps in switching from ROCK2-mediated to MRCKα-mediated cell contractility. ICAP-1 monoubiquitylation serves as a molecular switch to coordinate extracellular matrix density and rigidity sensing thus acting as a crucial modulator of cell migration and mechanosensing.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

ICAP-1 monoubiquitylation coordinates matrix density and rigidity sensing for cell migration through ROCK2–MRCKα balance

Bouin

Kyumurkov

Régent-Kloeckner

et al. 2017

Journal of Cell Science

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“…It is possible that, following the loss of the synergy site, integrins are actively transitioned into a closed inactive conformation and trafficked out of adhesion sites through the action of negative regulators of integrin activation, such as sharpin, filamin or ICAP1 (also known as ITGB1BP1). Interestingly, ICAP1-mediated regulation of b1 integrin activation has recently been linked to both aberrant vasculogenesis and ECM remodeling (Faurobert et al, 2013). Our data suggest that, following anastellin treatment, the avb5 integrins function to maintain adhesion as well as the activation of integrin-associated signaling proteins, whereas a5b1-specific functions are selectively inhibited.…”

Section: Discussionmentioning

confidence: 52%

Conformational remodeling of the fibronectin matrix selectively regulates VEGF signaling

Ambesi

McKeown‐Longo

2014

Journal of Cell Science

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The fibronectin matrix plays a crucial role in the regulation of angiogenesis during development, tissue repair and pathogenesis. Previous work has identified a fibronectin-derived homophilic binding peptide, anastellin, as an effective inhibitor of angiogenesis; however, its mechanism of action is not well understood. In the present study, we demonstrate that anastellin selectively inhibits microvessel cell signaling in response to the VEGF 165 isoform, but not VEGF 121 , by preventing the assembly of the complex containing the VEGF receptor and neuropilin-1. Anastellin treatment resulted in the inactivation of a5b1 integrins but was not accompanied by a change in either adhesion complexes or adhesion-based signaling. Integrin inactivation was associated with a masking of the fibronectin synergy site within the extracellular matrix (ECM), indicating that a5b1 inactivation resulted from a decrease in available ligand. These data demonstrate that anastellin influences the microvessel cell response to growth factors by controlling the repertoire of ligated integrins and point to anastellin as an effective regulator of fibronectin matrix organization. These studies further suggest that homophilic fibronectin binding peptides might have novel applications in the field of tissue regeneration as tools to regulate neovascularization.

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“…For example, Cdk5 is required cellautonomously in both (Hirasawa et al, 2004;Ohshima et al, 2007), Dab1 is required only in migrating neurons (Franco et al, 2011), whereas β1 integrins (Belvindrah et al, 2007) and RhoA (Cappello et al, 2012) are radial glia specific. Ccm3 (this study) and Itgb1 mutants display neuronal migration and cortical lamination defects (Graus-Porta et al, 2001;Schmid et al, 2004;Huang et al, 2006;Marchetti et al, 2010), pial detachment of endfeet (Graus-Porta et al, 2001;Kwon et al, 2011) and reactive gliosis (Robel et al, 2009), suggesting a -possibly indirectinteraction that warrants investigation, especially given the association of CCM1 with ICAP1α, which binds the β1 integrin cytoplasmic tail (Zawistowski et al, 2002;Faurobert et al, 2013). On the other hand, RhoA is necessary in radial glia to stabilize the actin and microtubule cytoskeletons, and to maintain the radial glia scaffold (Cappello et al, 2012); thus, our findings that RhoA is activated in Ccm3 conditional mutants could partially explain the migration defects.…”

Section: Discussionmentioning

confidence: 99%

Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration

2014

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Loss of function of cerebral cavernous malformation 3 (CCM3) results in an autosomal dominant cerebrovascular disorder. Here, we uncover a developmental role for CCM3 in regulating neuronal migration in the neocortex. Using cell type-specific gene inactivation in mice, we show that CCM3 has both cell autonomous and cell nonautonomous functions in neural progenitors and is specifically required in radial glia and newly born pyramidal neurons migrating through the subventricular zone, but not in those migrating through the cortical plate. Loss of CCM3 function leads to RhoA activation, alterations in the actin and microtubule cytoskeleton affecting neuronal morphology, and abnormalities in laminar positioning of primarily late-born neurons, indicating CCM3 involvement in radial glia-dependent locomotion and possible interaction with the Cdk5/RhoA pathway. Thus, we identify a novel cytoplasmic regulator of neuronal migration and demonstrate that its inactivation in radial glia progenitors and nascent neurons produces severe malformations of cortical development.

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CCM1–ICAP-1 complex controls β1 integrin–dependent endothelial contractility and fibronectin remodeling

Abstract: Loss of CCM1/2 leads to destabilization of ICAP-1 and up-regulation of β1 integrin, resulting in the destabilization of intercellular junctions due to increased cell contractility and aberrant extracellular matrix remodeling.

Cited by 94 publications

References 82 publications

ICAP-1 monoubiquitylation coordinates matrix density and rigidity sensing for cell migration through ROCK2–MRCKα balance

ICAP-1 monoubiquitylation coordinates matrix density and rigidity sensing for cell migration through ROCK2–MRCKα balance

Conformational remodeling of the fibronectin matrix selectively regulates VEGF signaling

Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration

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