FERMT2 cleavage impacts APP metabolism in a Src‐dependent manner

Background FERMT2 has been identified as a genetic risk factor for AD. We have reported that the FERMT2 protein is a partner of APP and a loss of FERMT2 (kindlin‐2) function altered both axonal growth and long‐term potentiation in an APP‐dependent manner. In this study, we aimed to identify the molecular mechanisms leading to loss of FERMT2 function. Method We aimed to identify proteases and other factors that regulate the cleavage of FERMT2 protein, which appears to be a mechanism that modulates its functions. The impact on FERMT2 cleavage and molecular interactions were analyzed by Co‐IP and WB. Consequences of these molecular interactions between FERMT2 and its partners on APP metabolism were then investigated using HEK‐APP cell lines. Result We identified a caspase‐dependent cleavage of FERMT2 that could be a molecular mechanism involved in the regulation of cell adhesion processes by inhibiting the ability of FERMT2 to interact with its partners. Furthermore, these results suggest that c‐Src activity, already known to regulate FERMT2 pathway, may have an impact on APP metabolism through regulation of FERMT2 cleavage. Conclusion Altogether, our data provide new mechanisms for understanding the involvement of the genetic risk factor FERMT2 in the pathophysiological processes of AD.