Interaction between krit1 and icap1α infers perturbation of integrin β1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation

Jun Zhang, Richard E. Clatterbuck, Daniele Rigamonti, David D. Chang, Harry C. Dietz

Research output: Contribution to journalArticlepeer-review

Abstract

Cerebral cavernous malformation (CCM) is a common autosomal dominant disorder characterized by venous sinusoids that predispose to intracranial hemorrhage. CCM is genetically heterogeneous, with loci at 7q, 7p and 3q. Mutations in KRIT1 account for all cases linked to 7q (CCM1), but the pathogenesis of CCM is not understood. Krev Interaction Trapped 1 (krit1) was originally identified through its interaction with the Ras-family GTPase krev1/rap1a in a two-hybrid screen, inferring a role in GTPase signaling cascades. We demonstrated additional 5′-coding exons for krit1, extending the N-terminus by 207 amino acids compared to the previously reported protein. Remarkably, by two-hybrid analysis and coimmunoprecipitation, full-length krit1 fails to interact with krev1/rap1a but shows strong interaction with integrin cytoplasmic domain-associated protein-1 (icap1). Icap1 binds to a NPXY motif in the cytoplasmic domain of β1 integrin and participates in β1-mediated cell adhesion and migration. The novel N-terminus of krit1 contains a NPXY motif that it is required for icap1 interaction. Like β1 integrin, krit1 interacts with the 200 amino acid isoform of icap1 (icap1α), but not a 150 amino acid form that results from alternative splicing (icap1β). In a competition assay, induced expression of krit1 diminishes the interaction between icap1α and β1 integrin. Taken together, these data suggest that β1 integrin and krit1 compete for the same site on icap1α, perhaps constituting a regulatory mechanism. Loss-of-function KRIT1 mutations, as observed in CCM1, would shift the balance with predicted consequences for endothelial cell performance during integrin β1-dependent angiogenesis.

Original languageEnglish (US)
Pages (from-to)2953-2960
Number of pages8
JournalHuman molecular genetics
Volume10
Issue number25
StatePublished - Dec 1 2001

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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