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Human Molecular Genetics, 2002, Vol. 11, No. 4 389-396
© 2002 Oxford University Press

KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis

Jon S. Zawistowski, Ilya G. Serebriiskii1, Maximilian F. Lee2, Erica A. Golemis1 and Douglas A. Marchuk+

Department of Genetics, Duke University Medical Center, Durham, NC 27710, USA, 1Division of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA and 2Department of Pediatrics, New York University Medical Center, New York, NY 10016, USA

Mutations in KRIT1, a protein initially identified based on a yeast two-hybrid interaction with the RAS-family GTPase RAP1A, are responsible for the development of the inherited vascular disorder cerebral cavernous malformations (CCM1). As the function of the KRIT1 protein and its role in CCM pathogenesis remain unknown, we performed yeast two-hybrid screens to identify additional protein binding partners. A fragment containing the N-terminal 272 amino acid residues of KRIT1, a region lacking similarity to any known protein upon database searches, was used as bait. From parallel screens of human fetal brain and HeLa cDNA libraries, we obtained multiple independent isolates of human integrin cytoplasmic domain-associated protein-1 (ICAP-1) as interacting clones. The interaction of KRIT1 and ICAP-1 was confirmed by GST-KRIT1 trapping of endogenous ICAP-1 from 293T cells. The {alpha} isoform of ICAP-1 is a 200 amino acid serine/threonine-rich phosphoprotein which binds the cytoplasmic tail of ß1 integrins. We show that mutagenesis of the N-terminal KRIT1 NPXY amino acid sequence, a motif critical for ICAP-1 binding to ß1 integrin molecules, completely abrogates the KRIT1/ICAP-1 interaction. The interaction between ICAP-1 and KRIT1, and the presence of a FERM domain in the latter, suggest that KRIT1 might be involved in the bidirectional signaling between integrin molecules and the cytoskeleton. Furthermore, these data suggest that KRIT1 might affect cell adhesion processes via integrin signaling in CCM1 pathogenesis.

+ To whom correspondence should be addressed. Tel: +1 919 684 3290; Fax: +1 919 681 9193; Email: march004@mc.duke.edu


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