The Rap1-RIAM-talin axis of integrin activation and blood cell function

Abstract

Integrin adhesion receptors mediate the adhesion of blood cells, such as leukocytes, to other cells, such as endothelial cells. Integrins also are critical for anchorage of hematopoietic precursors to the extracellular matrix. Blood cells can dynamically regulate the affinities of integrins for their ligands ("activation"), an event central to their functions. Here we review recent progress in understanding the mechanisms of integrin activation with a focus on the functions of blood cells. We discuss how talin binding to the integrin β cytoplasmic domain, in conjunction with the plasma membrane, induces long-range allosteric rearrangements that lead to integrin activation. Second, we review our understanding of how signaling events, particularly those involving Rap1 small guanosine triphosphate (GTP)hydrolases, can regulate the talin-integrin interaction and resulting activation. Third, we review recent findings that highlight the role of the Rap1-GTP-interacting adapter molecule (RIAM), encoded by the APBB1IP gene, in leukocyte integrin activation and consequently in leukocyte trafficking.

Figure 1

Leukocyte trafficking depends on integrin activation. Leukocytes in flowing blood are captured by and roll via selectin ligand interactions. Selectin engagement signals talin-mediated integrin activation that leads to integrin extension and slowed rolling. Activation of the leukocytes, usually through G-protein–coupled receptors culminates in kindlin and talin-mediated arrest and subsequent leukocyte transmigration. Graphical art has been adapted from Les Laboratoires Servier © 2016.

Figure 2

A model of talin-dependent integrin activation. The tilt angle of β3 TMD is maintained by the interaction between the positively charged end of K716 and negatively charged-phosphate head group. TMD packing interaction of integrin αIIb and β3 is mediated through glycine residues (G972, G976 in αIIb and G708 in β3) in the middle of the TMDs. The TMD interaction is also stabilized by electrostatic interaction between D723 and R995. The membrane distal region of β3 cytoplasmic tail interacts with talin through an NPXY motif, which is part of the primary talin-binding site. The membrane proximal region of β3 cytoplasmic tail interacts with talin via hydrophobic interaction between two Phe residues (F727 and F730) in β3 and L325 in talin. The positively charged residues (K322, K272, K274, R277, and K256) on the surface of talin can interact with lipid bilayer. Talin binding to the β3 membrane proximal region and lipid bilayer increases the tilt angle of β3 TMD thereby disrupting the helical packing interaction of the TMD leading to their rearrangement and resulting long range conformational change in the integrin. The amino acid residues of integrin αIIb (blue), β3 (green), and talin1 (red) are numbered.

Figure 3

Hypothetical models of talin-independent integrin activation. (A) Translocation of integrins to lipid microdomains, distinct regions of the plasma membrane enriched in cholesterols and unsaturated lipids, can change the tilt angle of β3 TMD and disrupt the TMD interaction. (B) Stretch of lipid bilayer may change the properties of lipid bilayers, leading to the change in TMD tilt angle and disruption of the α-β TMD interaction. (C) When one of TMDs in the integrin molecule interacts with other TMDs, the α-β TMD interaction in the integrin can be disrupted. The disrupted α-β TMD interactions can then activate integrins.

Figure 4

The MRL protein-integrin-talin (MIT) complex forms the molecular basis of sticky fingers that direct cell migration. RIAM and its paralogue, lamellipodin, are the mammalian MRL proteins. (A) The MIT complex, visualized by bimolecular fluorescence complementation (green) between RIAM and integrin αIIbβ3, is enriched at the tips of growing actin filaments (red) in protruding regions of migrating cells. (B) Schematic representation of the MIT complex at the tips of sticky fingers. The N terminus of the MRL protein (RIAM or Lamellipodin) binds talin, thereby enabling its recruitment to the integrin to induce activation. The C terminus of MRL proteins increases processive actin polymerization in part by recruiting ENA/VASP and activators of the ARP2/3 complex to drive the rapid translocation of the integrins. Together, these 2 biochemical functions of the MRL proteins result in the formation of the sticky fingers at the cell edge that direct protrusion during cell migration. Scale bar: 5 μm. Adapted from Lagarrigue et al.