Structural and functional differences between KRIT1A and KRIT1B isoforms: A framework for understanding CCM pathogenesis

Francalanci, Floriana; Avolio, Maria; Luca, Elisa De; Longo, Dario Livio; Menchise, Valeria; Guazzi, Paolo; Sgrò, Francesco; Marino, Marco; Gallelli, Luca; Balzac, Fiorella; Trabalzini, Lorenza; Retta, Saverio Francesco

doi:10.1016/j.yexcr.2008.10.006

Cited by 49 publications

(68 citation statements)

References 55 publications

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“…6A). These data are consistent with reports that KRIT1 drives ICAP1 nuclear localization (28). However, neither DsRed-ICAP1 ⌬NLS nor DsRed-ICAP1 NLSmut showed any significant changes in localization when co-expressed with either GFP-KRIT1 Nterm or GFP-KRIT1 Nterm/ICAP1 (Fig.…”

Section: Binding To Icap1 Drives Nuclear Localization Of the Nterminasupporting

confidence: 93%

“…Additionally, data from other laboratories suggest that KRIT1 localization drives ICAP1 localization (28). To test whether cellular localization might play a role in the reversal of ICAP1-mediated integrin suppression by KRIT1, we co-expressed GFP or GFP-tagged KRIT1 Nterm with DsRed or DsRedtagged ICAP1 in CHO cells and evaluated nuclear localization in double positive cells.…”

Section: Binding To Icap1 Drives Nuclear Localization Of the Nterminamentioning

confidence: 99%

“…However, KRIT1 is a multidomain protein that, in addition to having several other binding partners, contains two putative NLS and one predicted nuclear export signal (NES) (Fig. 7A) (17,28,30,43,44). To determine the localization of full-length KRIT1 (KRIT1 FL ) and the role of the predicted NLS and NES in the absence of co-expressed ICAP1, GFP-tagged KRIT1 was overexpressed in CHO cells (which do not express either endogenous ICAP1 or KRIT1 (45)).…”

Section: Binding To Icap1 Drives Nuclear Localization Of the Nterminamentioning

confidence: 99%

“…ICAP1 and KRIT1 shuttle between the nucleus and cytoplasm, and putative nuclear localization signals (NLS) have been identified in both proteins (27)(28)(29). However, very little is understood about shuttling dynamics or its cellular significance.…”

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confidence: 99%

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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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Section: Binding To Icap1 Drives Nuclear Localization Of the Nterminasupporting

confidence: 93%

Section: Binding To Icap1 Drives Nuclear Localization Of the Nterminamentioning

confidence: 99%

Section: Binding To Icap1 Drives Nuclear Localization Of the Nterminamentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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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“…ICAP1-mediated nuclear translocation of CCM1 is dominant over the cytoplasmic localization induced by CCM2. 138 What function is mediated by nuclear CCM1 is however at present completely unknown.…”

Section: Spatial Regulation Of Ccm1mentioning

confidence: 99%

CCM1 and the second life of proteins in adhesion complexes

Berg

Burgering

2014

Cell Adhesion & Migration

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Review of familial cerebral cavernous malformations and report of seven additional families

Vos

Vreeburg

Koek

et al. 2016

American J of Med Genetics Pt A

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Cerebral cavernous malformations are vascular anomalies of the central nervous system characterized by clusters of enlarged, leaky capillaries. They are caused by loss-of-function mutations in KRIT1, CCM2, or PDCD10. The proteins encoded by these genes are involved in four partially interconnected signaling pathways that control angiogenesis and endothelial permeability. Cerebral cavernous malformations can occur sporadically, or as a familial autosomal dominant disorder (FCCM) with incomplete clinical and neuroradiological penetrance and great inter-individual variability. Although the clinical course is unpredictable, symptoms typically present during adult life and include headaches, focal neurological deficits, seizures, and potentially fatal stroke. In addition to neural lesions, extraneural cavernous malformations have been described in familial disease in several tissues, in particular the skin. We here present seven novel FCCM families with neurologic and cutaneous lesions. We review histopathological and clinical features and provide an update on the pathophysiology of cerebral cavernous malformations and associated cutaneous vascular lesions. © 2016 Wiley Periodicals, Inc.

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Structural and functional differences between KRIT1A and KRIT1B isoforms: A framework for understanding CCM pathogenesis

Cited by 49 publications

References 55 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

Review of familial cerebral cavernous malformations and report of seven additional families

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