Abstract:
:Activation of Rap1 small GTPases stabilizes cell--cell junctions, and this activity requires Krev Interaction Trapped gene 1 (KRIT1). Loss of KRIT1 disrupts cardiovascular development and causes autosomal dominant familial cerebral cavernous malformations. Here we report that native KRIT1 protein binds the effector loop of Rap1A but not H-Ras in a GTP-dependent manner, establishing that it is an authentic Rap1-specific effector. By modeling the KRIT1-Rap1 interface we designed a well-folded KRIT1 mutant that exhibited a ~40-fold-reduced affinity for Rap1A and maintained other KRIT1-binding functions. Direct binding of KRIT1 to Rap1 stabilized endothelial cell-cell junctions in vitro and was required for cardiovascular development in vivo. Mechanistically, Rap1 binding released KRIT1 from microtubules, enabling it to locate to cell--cell junctions, where it suppressed Rho kinase signaling and stabilized the junctions. These studies establish that the direct physical interaction of Rap1 with KRIT1 enables the translocation of microtubule-sequestered KRIT1 to junctions, thereby supporting junctional integrity and cardiovascular development.
journal_name
Mol Biol Celljournal_title
Molecular biology of the cellauthors
Liu JJ,Stockton RA,Gingras AR,Ablooglu AJ,Han J,Bobkov AA,Ginsberg MHdoi
10.1091/mbc.E11-02-0157subject
Has Abstractpub_date
2011-07-15 00:00:00pages
2509-19issue
14eissn
1059-1524issn
1939-4586pii
mbc.E11-02-0157journal_volume
22pub_type
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