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Brahme migration, embryonic development, More recently, human disease and David A. Calderwood* tissue formation, vasculogenesis, mutations and knockout studies have inflammatory and immune responses, implicated a second family of The ability of metazoan cells to and wound healing [1]. Like other FERM-domain proteins, the kindlins, in sense and adhere to the insoluble cell-surface receptors, integrins integrin activation [5–7]. Kindlins bind extracellular matrix (ECM) that can be regulated by controlling to the b integrin cytoplasmic tail, surrounds them is central to cell-surface delivery, endocytosis, specifically to the membrane-distal multicellular life. Integrins, the major and subsequent recycling or NPxY motif and its preceding family of ECM adhesion receptors degradation. Indeed, the importance threonines (Figure 1), and kindlin responsible for this ability, are of integrin internalization and recycling deficiency leads to defects in integrin transmembrane ab heterodimers that in a range of cellular processes is activation and signaling. However, the link the ECM to intracellular increasingly well appreciated [2,3]. molecular basis for kindlin function is cytoskeletal and signaling networks. However, a unique and defining feature not understood. In this issue of Current Integrins are thus integral to a range of integrin regulation is integrin Biology, Margadant et al. [8] provide of essential processes, including cell activation — the allosteric transition new insights into the differential roles Dispatch R693 of talin and kindlin in b1 integrin Talin Kindlin A regulation and for the first time link 1A: KLLMIIHDRREFAKFEKEKMNAKWDTGENPIYKSAVTTVVNPKYEGK kindlins to the control of lysosomal Sorting nexin-17 degradation of integrins. Using alternative approaches, two other B Active Inactive recent papers [9,10] also reveal a role integrin integrin for the kindlin-binding NPxY motif in 1 determining whether integrins are 5 lysosomally degraded or are recycled to the cell surface. However, these investigators find that binding of the Talin FERM-domain-containing protein Kindlin sorting nexin 17 (SNX17) triggers recycling versus degradation. While many details remain to be elucidated, Early endosome and discrepancies resolved, taken together all three new papers suggest that the dynamics of FERM-domain binding to integrin NPxY motifs govern Recycling not only activation but also recycling endosome and degradation. Understanding how this occurs, if and how the processes SNX17 are linked, and how FERM-domain binding and competition are regulated will be the next challenges. Margadant et al. [8] investigated the Lysosome Current Biology roles of the talin- and kindlin-binding sites in b1 integrin activation and trafficking by reconstituting Figure 1. b-tail-binding proteins in integrin activation and sorting. embryoid-body-derived b1 (A) Amino acid sequence of the cytoplasmic tail of human b1 integrin. Regions important for integrin-null cells with wild-type b1or binding talin, kindlin and sorting nexin 17 (SNX17) are indicated, and key residues that were b mutated to disrupt these interactions are highlighted in red. (B) Model for regulation of integrin with 1 containing tyrosine to alanine activation and trafficking. Binding of talin and kindlin leads to integrin activation at the plasma mutations in the membrane-proximal membrane. Internalization leads to dissociation of talin and kindlin from integrin. SNX17 binds or membrane-distal NxxY motifs. integrins in early endosomes and, by an unknown mechanism, facilitates their recycling: integ- As expected, mutations in the rins unable to bind SNX17 are targeted for lysosomal degradation. Kindlin’s role in integrin talin-binding membrane-proximal trafficking remains controversial but kindlin and SNX17 can compete for binding to integrin NPxY motif result in defects in cell and they do not colocalize in the same subcellular compartment. Whether other tail-binding proteins regulate additional