Abstract
Integrins serve as conduits for the transmission of information between cells and their extracellular environment. Signaling across integrins is bidirectional, transducing both inside-out and outside-signaling. Integrin activation, a transition from a low affinity/avidity state to a high affinity/avidity state for cognate ligands, is an outcome of inside-signaling. Such activation is particularly important for the recognition of soluble ligands by blood cells but also influences cell-cell and cell-matrix interactions. Integrin activation depends on a complex series of interactions, which both accelerate and inhibit their interconversion from the low to the high affinity/avidity state. There are three components regarded as being most proximately involved in integrin activation: the integrin cytoplasmic tails, talins and kindlins. The participation of each of these molecules in integrin activation is highly regulated by post-translation modifications. The importance of targeted phosphorylation of integrin cytoplasmic tails and talins in integrin activation is well-established, but much less is known about the role of post-translational modification of kindlins. The kindlins, a three-member family of 4.1-ezrin-radixin-moesin (FERM)-domain proteins in mammals, bind directly to the cytoplasmic tails of integrin beta subunits. This commentary provides a synopsis of the emerging evidence for the role of kindlin phosphorylation in integrin regulation.
Highlights
Integrins, the subject of this collection, serve as primary portals of communication between cells and their extracellular environment
While many different molecular interactions are engaged as a consequence of integrin activation leading to the formation of nascent focal adhesions and maturation into multi-molecular adhesomes [6], three molecules are recognized as being key to and directly engaged in the activation of most integrins: (i) the integrin itself where changes are initiated in their cytoplasmic tails (CT) [7]; (ii) talin, a large cytoskeletal protein composed of a 4.1-ezrin-radixin-moesin (FERM) domain that resides in the talin head and a long, multi-helical bundle; and (iii) a kindlin, a three-member family of proteins composed of a family of 4.1-ezrin-radixin-moesin (FERM) domain intersected by a PH domain [8]
Bidirectional signaling across integrins relies heavily upon post-translational modifications (PTMs) with protein phosphorylation being prominent
Summary
The subject of this collection, serve as primary portals of communication between cells and their extracellular environment. Productive inside-out signaling results in integrin activation, a transition from a low affinity/avidity state to a high affinity/avidity state for cognate ligands. Such activation is important for the recognition of soluble ligands by blood cell integrins and for certain cell–cell and cell–matrix interactions (e.g., [1,2,3,4,5]). Bidirectional signaling across integrins relies heavily upon post-translational modifications (PTMs) with protein phosphorylation being prominent. Within the integrin activation triumvirate of integrin β CT, talin and kindlin, each component is subject phosphorylation. The functional significance of PTM of kindlins controlling integrin signaling is beginning to be recognized. After a brief summary of the kindlins structure, this commentary focuses on this emerging evidence that PTM of kindlins plays significant roles in integrin activation
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