Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 5, Pages 1884-1898Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.762393
Keywords
cell compartmentalization; cerebral cavernous malformation; integrin; KRIT1 (Krev interaction trapped); protein targeting; ICAP1 (integrin cytoplasmic domain-associated protein)
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Funding
- National Institutes of Health Grants [R01NS085078, F32HL127948]
- American Cancer Society Grant [122171-PF-12-051-01-CSM]
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Binding 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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