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J Biol Chem. 2017 Feb 3;292(5):1884-1898. doi: 10.1074/jbc.M116.762393. Epub 2016 Dec 21.

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

Author information

1
From the Department of Pharmacology and.
2
From the Department of Pharmacology and david.calderwood@yale.edu.
3
the Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520.

Abstract

Binding of ICAP1 (integrin cytoplasmic domain-associated protein-1) to the cytoplasmic tails of β1 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 β1 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.

KEYWORDS:

ICAP1 (integrin cytoplasmic domain-associated protein); KRIT1 (Krev interaction trapped); cell compartmentalization; cerebral cavernous malformation; integrin; protein targeting

PMID:
28003363
PMCID:
PMC5290960
DOI:
10.1074/jbc.M116.762393
[Indexed for MEDLINE]
Free PMC Article

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