Kindlins in FERM adhesion

Abstract

The Kindlin family of intracellular proteins has recently emerged as key regulators of cellular functions and cell-matrix interactions. The 3 members of this family, Kindlin-1, -2, and -3, perform an essential role in activation of integrin adhesion receptors, and expression of at least 1 Kindlin paralog is required to enable integrin activation in physiologically relevant settings. In humans, deficiencies in Kindlin-3 lead to a number of abnormalities affecting hemostasis, the immune system, and bone function, whereas the lack of Kindlin-1 causes profound skin defects. The importance of Kindlins is underscored by the results of animal knockout studies, which clearly show the indispensable and nonredundant functions of all 3 Kindlins in development and normal physiology. This review discusses recent progress in the studies of Kindlin protein family, emphasizing newly identified functions and potential mechanisms underlying differential activities of the family members.

Figure 1

Schematic representation of the signaling pathway from an agonist stimulation to integrin activation. CalDAG GEFI, a GDP/GTP exchange factor specific for Rap small G proteins, and protein kinase C (PKC) activated by a receptor-dependent stimulation of phospholipase C. As a result, Rap1*GTP interaction with RIAM protein (not shown) stimulates talin-1 function in the inside-out pathway. Protein kinase C has been implicated in the signaling as well, although the substrates important for the signaling are currently unknown. Talin-1 and Kindlin FERM domain are shown as spheres with 3 subdomains; the intersecting PH domain in Kindlin is shown as the dark-colored segment.

Figure 2

Schematic representation of the Kindlin protein family in mammals. Tissue distribution and consequences of Kindlins' loss in animal models and human genetic disorders are shown side by side for comparison.

Figure 3

Schematic domain architecture of Kindlins. Overlap of the defined subdomains with the conserved and nonconserved regions. F0, F1, F2, and F3 indicate subdomains of the FERM domain; and PH, pleckstrin homology domain. Variable region (V) intersects the F1 subdomain, splitting it into 2 parts. PH domain intersects the F2 subdomain. Numbers of Kindlin-3 amino acid residues are shown on the top.

Figure 4

Molecular mechanisms of Glanzmann thrombasthenia and leukocyte adhesion deficiency syndrome in contrast to bleeding and immune disorder caused by Kindlin-3 deficiency (shown on blue background on the bottom). Mechanisms of normal platelet and leukocyte functions are shown on yellow background in the far left and right columns, respectively.

Figure 5

Schematic representation of hematopoietic and mesenchymal cell differentiation in bone marrow. Cell types affected by the loss of Kindlin-3 and the functional consequences in human subjects leading to a number of clinical manifestations, including immune defects, osteopetrosis, and bleeding.