In this issue of Blood, Pluskota et al have defined a completely novel role for Kindlin.1 This protein has been known for decades, but apparently it still has a few new tricks up its sleeve.
Almost 60 years ago, Dr Theresa Kindler described a rare autosomal recessive disorder of hyperkeratosis and hyperpigmentation.2 Children with this inherited disorder have skin blistering on their extremities that is induced by minimal trauma (see figure). Photosensitivity is often present. As individuals with Kindler syndrome age, the blistering improves, but they develop changes in the pigmentation of their skin and cutaneous atrophy. The disease is associated with frequent cutaneous infections, but intelligence and lifespan are normal.
In 2003, work that was performed simultaneously by 2 independent groups demonstrated that mutations within kindlin cause this disorder.3,4 Because Kindlin turned out to have 2 additional isoforms, this small family of proteins is now referred to as Kindlin-1, -2, and -3. The 3 isoforms of Kindlin have unique tissue expression patterns and therefore play individual roles in biology (see figure). These discrete tissue distributions, along with naturally occurring mutations in humans and engineered mutations in mice, have given us clues about the functions of each of the individual Kindlin isoforms.
Kindlin-1 is only expressed in epithelial cells, and the mutations within the Kindlin-1 gene lead to a disease of skin blistering and, ultimately, cutaneous atrophy. These mutations appear to be attributable to the failure of the cutaneous basal cells to tightly adhere to the lamina densa.
Kindlin-2 is found in the mesenchymal cells, which include the endothelial cells. There are no human mutations known to occur in the Kindlin-2 gene. However, mutations that are engineered into the mouse Kindlin-2 gene cause embryonic lethality in the peri-implantation period. It is notable that endothelial cells that even partially lack the Kindlin-2 have defective cell adhesion.
Last, the third isoform of Kindlin, called Kindlin-3, is exclusively expressed in hematopoietic cells. Mutations within the Kindlin-3 gene lead to a type of the human disease called leukocyte adhesion deficiency type III. This is a disorder of both white blood cells and platelets that is characterized by infections and bleeding. Blood cells lacking Kindlin-3 also have a defect in adhesion.
The diseases that are associated with Kindlin mutations all have defects in cell adhesion. This is because Kindlin is required to regulate a family of adhesion receptors, which are called integrins. Integrins are a specific family of adhesion receptors that are deemed to be “integral” to life. Integrins not only allow cells to adhere to substrates or to other cells, but are also indirectly essential for diverse biologic processes that include cell motility, cytoskeletal organization, cell survival, gene transcription, and cell proliferation.
Integrins do not efficiently bind their extracellular substrates unless intracellular kindlin is stuck to the cytoplasmic tail of the 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 integrin-dependent 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-5′-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.