Doubling down on PKC benefits allogeneic BMT.

integrin (see figure). The binding of Kindlin to the integrin induces a conformational change in the integrin tail that facilitates the integrin to bind to another protein called Talin. Together, the binding of Kindlin and Talin to an integrin induces changes that allow the integrin to bind to its ligand. Until now, it appeared that the Kindlin-associated diseases—Kindler syndrome and leukocyte adhesion deficiency type III—were due to an inability of integrin adhesion receptors to do their job. Pluskota et al have now uncovered another role for kindlins. When they analyzed mice heterozygous for the Kindlin-2 knockout mutation, they observed that the adhesion of the their platelets to the endothelium was impaired. This finding is just as one would predict because this association is an integrindependent phenomenon. What was not predicted was that this defective adhesion did not have anything to do with the activation of integrins. Instead, it was due to the increased surface expression on endothelial cells of 2 enzymes that are involved in adenine nucleotide degradation: adenosine triphosphate diphosphohydrolase (CD39) and ecto-59-endonucleotidase (CD73). This surprising finding was due to the binding of Kindlin-2 to a component of the clathrin complex. This binding mechanism enabled Kindlin-2 to regulate the endocytosis and recycling of CD39 and CD73 on the endothelial cell surface (see figure). Kindlin family members are certainly critical components of integrin receptor activation, and mutations within the Kindlins gene can cause a variety of human diseases. The work presented in this issue of Blood demonstrates that Kindlins have an additional function that does not involve integrins, but instead regulates endocytosis and the recycling of cell-surface receptors. Based on this work, it would be worthwhile to determine whether patients with kindlin mutations have defects in endocytosis. It will also be interesting to determine whether there are even more functions for this fascinating family of proteins. Conflict-of-interest disclosure:The author declares no competing financial interests. n