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Human Molecular Genetics, 2001, Vol. 10, No. 25 2953-2960
© 2001 Oxford University Press

Interaction between krit1 and icap1{alpha} infers perturbation of integrin ß1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation

Jun Zhang, Richard E. Clatterbuck1, Daniele Rigamonti1, David D. Chang2 and Harry C. Dietz+

Howard Hughes Medical Institute and The Institute of Genetic Medicine, 1Department of Neurological Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and 2Department of Medicine, Department of Microbiology, Department of Immunology, Department of Molecular Genetics and Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, CA 90095, USA

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 co-immunoprecipitation, 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 ß1 integrin and participates in ß1-mediated cell adhesion and migration. The novel N-terminus of krit1 contains a NPXY motif that it is required for icap1 interaction. Like ß1 integrin, krit1 interacts with the 200 amino acid isoform of icap1 (icap1{alpha}), but not a 150 amino acid form that results from alternative splicing (icap1ß). In a competition assay, induced expression of krit1 diminishes the interaction between icap1{alpha} and ß1 integrin. Taken together, these data suggest that ß1 integrin and krit1 compete for the same site on icap1{alpha}, 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 ß1-dependent angiogenesis.

+ To whom correspondence should be addressed at: The Johns Hopkins University School of Medicine, Ross 858, 720 Rutland Avenue, Baltimore, MD 21205, USA. Tel: +1 410 614 0701; Fax: +1 410 614 2256; Email: hdietz@jhmi.edu


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