title: Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences β1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus.
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.
authors.affiliation: From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Draheim
authors.affiliation: From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Huet-Calderwood
authors.affiliation: From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Simon
authors.affiliation: From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520; the Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520. Electronic address: david.calderwood@yale.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Calderwood
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016466:CHO Cells; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000075927:KRIT1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C108257:ITGB1BP1 protein, human; D019012:Integrin beta1; D047908:Intracellular Signaling Peptides and Proteins; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins
keywords: ICAP1 (integrin cytoplasmic domain-associated protein); KRIT1 (Krev interaction trapped); cell compartmentalization; cerebral cavernous malformation; integrin; protein targeting