Mechanism for KRIT1 Release of ICAP1-Mediated Suppression of Integrin Activation

Liu, Weizhi; Draheim, Kyle; Zhang, Rong; Calderwood, David A.; Boggon, Titus J.

doi:10.1016/j.molcel.2012.12.005

Cited by 76 publications

(150 citation statements)

References 47 publications

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“…Notably, negative regulators that bind the integrin cytoplasmic domain and prevent talin or kindlin binding can counteract talin and kindlinmediated integrin activation (7,8). Here we report our investigation of one such negative regulator, integrin cytoplasmic domain-associated protein-1 (ICAP1).…”

mentioning

confidence: 98%

Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences β1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus

Draheim

Huet-Calderwood

Simon

et al. 2017

Journal of Biological Chemistry

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Edited by Thomas SöllnerBinding of ICAP1 (integrin cytoplasmic domain-associated protein-1) to the cytoplasmic tails of ␤1 integrins inhibits integrin activation. ICAP1 also binds to KRIT1 (Krev interaction trapped-1), a protein whose loss of function leads to cerebral cavernous malformation, a cerebrovascular dysplasia occurring in up to 0.5% of the population. We previously showed that KRIT1 functions as a switch for ␤1 integrin activation by antagonizing ICAP1-mediated inhibition of integrin activation. Here we use overexpression studies, mutagenesis, and flow cytometry to show that ICAP1 contains a functional nuclear localization signal and that nuclear localization impairs the ability of ICAP1 to suppress integrin activation. Moreover, we find that ICAP1 drives the nuclear localization of KRIT1 in a manner dependent upon a direct ICAP1/KRIT1 interaction. Thus, nuclear-cytoplasmic shuttling of ICAP1 influences both integrin activation and KRIT1 localization, presumably impacting nuclear functions of KRIT1.

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mentioning

confidence: 98%

Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences β1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus

Draheim

Huet-Calderwood

Simon

et al. 2017

Journal of Biological Chemistry

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“…For example, ICAP1 can compete with talin and kindlin for binding to β1-integrins. 10 Filamin is another inhibitory protein of integrins, it interacts with the NXXY motif in β integrin tails, and thereby, inhibits talin binding ( Fig. 1 [2]; reviewed in ref.…”

Section: Integrin Signalingmentioning

confidence: 99%

“…[69][70][71] ICAP1 binds to the cytoplasmic domain of integrin β1, and thereby, prevents binding of talin [72][73][74] and kindlin. 10,75 Binding of talin and kindlin to integrin β1 is essential for proper integrin-mediated cell adhesion and formation of focal adhesions; 76 hence, inhibition of this binding disrupts proper cell adhesion. Binding of ICAP1 to β1-integrins is mutually exclusive with its binding to CCM1.…”

Section: Ccm1 In Integrin Signalingmentioning

confidence: 99%

“…2 [2]). ICAP1 mediates stability of CCM1 by binding the first NPxY motif of CCM1 (CCM1 contains three NPxY motifs 10 ), resulting in an open and more stable conformation.…”

Section: Ccm1 In Integrin Signalingmentioning

confidence: 99%

“…10,75 This subsequently inhibits proper formation of focal adhesions. ICAP1α acts as a negative regulator of integrin function by competing with kindlin for binding to the β1-intergrin tail.…”

Section: Spatial Regulation Of Ccm1mentioning

confidence: 99%

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Vascular anomalies are separated into vascular tumours and vascular malformations. Vascular malformations are named according to the affected type of vessels, that is venous, capillary, arteriovenous or lymphatic malformations. Up to now, sclerotherapy, embolisation and/or surgery are the treatments of choice, yet they do not often offer a curative treatment. Thus, there is an important need to develop novel disease‐specific therapeutic approaches. Inherited forms of vascular malformations led to the identification of several genes that are mutated encoding dysfunctional proteins. Demonstration that tissular second hits are commonly involved in inherited forms to explain development of lesions led to study somatic mutations in sporadically occurring forms. Since the primary discovery demonstrating that venous malformations are due to somatic mutations in TIE2/TEK, most types of vascular anomalies now have a known genetic cause. Thereby, the signalling pathways involved have been unravelled, leading to a better understanding of the aetiopathogenesis of vascular anomalies. As – like in cancers – the RAS/MAPK/ERK and the PI3K/AKT/mTOR signalling are enhanced in most vascular anomalies, treatment with cancer drugs interfering with these pathways could represent novel treatment options. Key Concepts Vascular anomalies are classified into tumours and malformations. The latter are further divided according to the affected vessels to capillary, venous, arterial, lymphatic and combined malformations. Treatment options are mostly restricted to sclerotherapy, embolisation and/or surgery. Most vascular anomalies are caused by genetic mutations, either germ line or somatic. Altered signalling involves RAS/MAPK/ERK, BMP9/10/ALK, PI3K/AKT/mTOR and VEGF/VEGFR3 pathways. Same pathways are also involved in cancers. Making repurposing of cancer drugs that interfere with these pathways, such as the mTOR inhibitor rapamycin, of interest for the treatment of vascular anomalies.

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Mechanism for KRIT1 Release of ICAP1-Mediated Suppression of Integrin Activation

Cited by 76 publications

References 47 publications

Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences β1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus

Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences β1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus

CCM1 and the second life of proteins in adhesion complexes

Molecular Genetics of Vascular Malformations

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