Krev-interaction trapped 1 (KRIT1) is an endothelial scaffold protein that promotes the stability of adherens junctions (AJs), and loss of its expression leads to cerebral cavernous malformations (CCMs). Several interaction partners of KRIT1 have been identified, including Rap1 and ICAP1α, a negative regulator of β1 integrin, but it is unclear how they contribute to AJ stability and maintenance. In this work, Harsha Swamy and Angela Glading (Swamy and Glading, 2022) systematically analyse the ability of a series of KRIT1 constructs to rescue barrier function in cells that have been depleted of KRIT1. These include KRIT1 mutants defective in binding to either Rap1 or ICAP1α, with the latter lacking the NPAY motif involved in intramolecular interactions between the N-terminus and the C-terminal phosphotyrosine-binding (PTB) domain. Using this panel of mutants, the authors show that, surprisingly, loss of the NPAY motif or disrupting the PTB domain is sufficient to restore endothelial barrier function. Moreover, they find that neither binding to Rap1 or ICAP1α, nor junctional localisation of KRIT1 is required for its ability to stabilise AJs. Instead, KRIT1 may act to regulate the location and magnitude of β1 integrin activation. This study thus points to a novel role for this integrin in endothelial barrier function, and further work will be needed to fully elucidate the underlying mechanisms.
