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

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

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.

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Adaptor Proteins, Signal Transducing
  • Animals
  • CHO Cells
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cricetinae
  • Cricetulus
  • HEK293 Cells
  • Humans
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • KRIT1 Protein
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • ITGB1BP1 protein, human
  • Integrin beta1
  • Intracellular Signaling Peptides and Proteins
  • KRIT1 Protein
  • KRIT1 protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins