Integrin avidity regulation: are changes in affinity and conformation underemphasized?

Integrins play critical roles in development, wound healing, immunity and cancer. Central to their function is their unique ability to modulate dynamically their adhesiveness through both affinity- and valency-based mechanisms. Recent advances have shed light on the structural basis for affinity regulation and on the signaling mechanisms responsible for both affinity and valency modes of regulation.

[1]  P. McEwan,et al.  Integrin structure: heady advances in ligand binding, but activation still makes the knees wobble. , 2003, Trends in biochemical sciences.

[2]  T. Springer,et al.  Conformational changes in tertiary structure near the ligand binding site of an integrin I domain. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Renhao Li,et al.  Activation of Integrin αIIbß3 by Modulation of Transmembrane Helix Associations , 2003, Science.

[4]  A. Galmiche,et al.  Conformation, Localization, and Integrin Binding of Talin Depend on Its Interaction with Phosphoinositides* , 2001, The Journal of Biological Chemistry.

[5]  Junichi Takagi,et al.  Locking in alternate conformations of the integrin αLβ2 I domain with disulfide bonds reveals functional relationships among integrin domains , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Junichi Takagi,et al.  Structures of the αL I Domain and Its Complex with ICAM-1 Reveal a Shape-Shifting Pathway for Integrin Regulation , 2003, Cell.

[7]  M. Arnaout,et al.  Does the Integrin αA Domain Act as a Ligand for its βA Domain? , 2002, Current Biology.

[8]  P. Altevogt,et al.  Integrin Leukocyte Function-associated Antigen-1-mediated Cell Binding Can Be Activated by Clustering of Membrane Rafts* , 1999, The Journal of Biological Chemistry.

[9]  N. Kieffer,et al.  Green fluorescent protein (GFP) tagged to the cytoplasmic tail of alphaIIb or beta3 allows the expression of a fully functional integrin alphaIIb(beta3): effect of beta3GFP on alphaIIb(beta3) ligand binding. , 2001, The Biochemical journal.

[10]  Keith Burridge,et al.  RhoA is required for monocyte tail retraction during transendothelial migration , 2001, The Journal of cell biology.

[11]  N. Hogg,et al.  A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta2 integrins Mac-1 and LFA-1. , 1999, The Journal of clinical investigation.

[12]  M. Shimaoka,et al.  Conformational regulation of integrin structure and function. , 2002, Annual review of biophysics and biomolecular structure.

[13]  P. McEwan,et al.  Conformational Changes in the Integrin βA Domain Provide a Mechanism for Signal Transduction via Hybrid Domain Movement* , 2003, The Journal of Biological Chemistry.

[14]  M. Schwartz,et al.  Rac recruits high-affinity integrin αvβ3 to lamellipodia in endothelial cell migration , 2001, Nature Cell Biology.

[15]  N. Minato,et al.  Rap1 Is a Potent Activation Signal for Leukocyte Function-Associated Antigen 1 Distinct from Protein Kinase C and Phosphatidylinositol-3-OH Kinase , 2000, Molecular and Cellular Biology.

[16]  R. Wolthuis,et al.  The Small Gtpase, Rap1, Mediates Cd31-Induced Integrin Adhesion , 2000, The Journal of cell biology.

[17]  Richard W. Farndale,et al.  Structural Basis of Collagen Recognition by Integrin α2β1 , 2000, Cell.

[18]  L. Piccio,et al.  Chemokines trigger immediate beta2 integrin affinity and mobility changes: differential regulation and roles in lymphocyte arrest under flow. , 2000, Immunity.

[19]  L. Parise,et al.  Relationships between Rap1b, Affinity Modulation of Integrin αIIbβ3, and the Actin Cytoskeleton* , 2002, The Journal of Biological Chemistry.

[20]  Junichi Takagi,et al.  Global Conformational Rearrangements in Integrin Extracellular Domains in Outside-In and Inside-Out Signaling , 2002, Cell.

[21]  Timothy A. Springer,et al.  Reversibly locking a protein fold in an active conformation with a disulfide bond: Integrin αL I domains with high affinity and antagonist activity in vivo , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[22]  C. Figdor,et al.  Avidity regulation of integrins: the driving force in leukocyte adhesion. , 2000, Current opinion in cell biology.

[23]  S. Singer.  Intercellular communication and cell-cell adhesion. , 1992, Science.

[24]  Timothy A. Springer,et al.  Association of the Membrane Proximal Regions of the α and β Subunit Cytoplasmic Domains Constrains an Integrin in the Inactive State* , 2001, The Journal of Biological Chemistry.

[25]  M. de Virgilio,et al.  Detection of Integrin αIIbβ3Clustering in Living Cells* , 2003, The Journal of Biological Chemistry.

[26]  Minsoo Kim,et al.  Bidirectional Transmembrane Signaling by Cytoplasmic Domain Separation in Integrins , 2003, Science.

[27]  N. Hogg,et al.  Mechanisms contributing to the activity of integrins on leukocytes , 2002, Immunological reviews.

[28]  Y. Matsuzawa,et al.  A Mutation in the Extracellular Cysteine-Rich Repeat Region of the β3 Subunit Activates Integrins IIbβ3 and Vβ3 , 1999 .

[29]  D. Webb,et al.  Differential Dynamics of α5 Integrin, Paxillin, and α-Actinin during Formation and Disassembly of Adhesions in Migrating Cells , 2001, The Journal of cell biology.

[30]  N. Hogg,et al.  Rap1A positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling , 2002, Nature Immunology.

[31]  P. A. McQueney,et al.  Flow cytometric measurement of kinetic and equilibrium binding parameters of arginine-glycine-aspartic acid ligands in binding to glycoprotein IIb/IIIa on platelets. , 1997, Cytometry.

[32]  J. Takagi,et al.  Stabilizing the open conformation of the integrin headpiece with a glycan wedge increases affinity for ligand , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[33]  M. Cybulsky,et al.  Detecting rapid and transient upregulation of leukocyte integrin affinity induced by chemokines and chemoattractants. , 2003, Journal of immunological methods.

[34]  N. Minato,et al.  Rap1 Functions as a Key Regulator of T-Cell and Antigen-Presenting Cell Interactions and Modulates T-Cell Responses , 2002, Molecular and Cellular Biology.

[35]  T. Tsuruo,et al.  Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow , 2003, The Journal of cell biology.

[36]  J. R. Huth,et al.  NMR and mutagenesis evidence for an I domain allosteric site that regulates lymphocyte function-associated antigen 1 ligand binding. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[37]  M. Shimaoka,et al.  Activation-induced Conformational Changes in the I Domain Region of Lymphocyte Function-associated Antigen 1* , 2002, The Journal of Biological Chemistry.

[38]  Junichi Takagi,et al.  Structure of integrin α5β1 in complex with fibronectin , 2003, The EMBO journal.

[39]  C. Figdor,et al.  The Small GTPase Rap1 Is Required for Mn2+- and Antibody-induced LFA-1- and VLA-4-mediated Cell Adhesion* , 2002, The Journal of Biological Chemistry.

[40]  M. Shimaoka,et al.  An isolated, surface-expressed I domain of the integrin αLβ2 is sufficient for strong adhesive function when locked in the open conformation with a disulfide bond , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[41]  R. Hynes,et al.  The Talin Head Domain Binds to Integrin β Subunit Cytoplasmic Tails and Regulates Integrin Activation* , 1999, The Journal of Biological Chemistry.

[42]  Junichi Takagi,et al.  Integrin activation and structural rearrangement , 2002, Immunological reviews.

[43]  M. Cybulsky,et al.  Chemoattractants Induce a Rapid and Transient Upregulation of Monocyte α4 Integrin Affinity for Vascular Cell Adhesion Molecule 1 Which Mediates Arrest , 2001, The Journal of experimental medicine.

[44]  Harold P. Erickson,et al.  C-terminal opening mimics 'inside-out' activation of integrin α5β1 , 2001, Nature Structural Biology.

[45]  N. Hogg,et al.  The involvement of lipid rafts in the regulation of integrin function. , 2002, Journal of cell science.

[46]  David A. Calderwood,et al.  Calpain Cleavage Promotes Talin Binding to the β3Integrin Cytoplasmic Domain* , 2001, The Journal of Biological Chemistry.

[47]  J. Takagi,et al.  High Affinity Ligand Binding by Integrins Does Not Involve Head Separation* , 2003, The Journal of Biological Chemistry.

[48]  K. Jacobson,et al.  Looking at lipid rafts? , 1999, Trends in cell biology.

[49]  H. Petty,et al.  Interactions of integrins with their partner proteins in leukocyte membranes , 2002, Immunologic research.

[50]  Timothy A. Springer,et al.  Structure and allosteric regulation of the αXβ2 integrin I domain , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[51]  David A. Calderwood,et al.  The Phosphotyrosine Binding-like Domain of Talin Activates Integrins* , 2002, The Journal of Biological Chemistry.

[52]  J M Miller,et al.  Adhesion-activating phorbol ester increases the mobility of leukocyte integrin LFA-1 in cultured lymphocytes. , 1996, The Journal of clinical investigation.

[53]  Michael L. Dustin,et al.  T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1 , 1989, Nature.

[54]  Wei Yang,et al.  Small molecule integrin antagonists that bind to the beta2 subunit I-like domain and activate signals in one direction and block them in the other. , 2003, Immunity.

[55]  J. Engel,et al.  Two-step binding mechanism of fibrinogen to alpha IIb beta 3 integrin reconstituted into planar lipid bilayers. , 1993, The Journal of biological chemistry.

[56]  Renhao Li,et al.  Oligomerization of the integrin αIIbβ3: Roles of the transmembrane and cytoplasmic domains , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[57]  N. Hogg,et al.  LFA-1–mediated Adhesion Is Regulated by Cytoskeletal Restraint and by a Ca2+-dependent Protease, Calpain , 1998, The Journal of cell biology.

[58]  J. Bos,et al.  Rap1 signalling: adhering to new models , 2001, Nature Reviews Molecular Cell Biology.

[59]  Stephen C. Blacklow,et al.  Cysteine-rich module structure reveals a fulcrum for integrin rearrangement upon activation , 2002, Nature Structural Biology.

[60]  Thilo Stehle,et al.  Crystal Structure of the Extracellular Segment of Integrin αVβ3 in Complex with an Arg-Gly-Asp Ligand , 2002, Science.

[61]  R. Fässler,et al.  Disruption of Focal Adhesions by Integrin Cytoplasmic Domain-associated Protein-1α* , 2003, The Journal of Biological Chemistry.

[62]  Thilo Stehle,et al.  Crystal Structure of the Extracellular Segment of Integrin αVβ3 , 2001, Science.

[63]  K. Katagiri,et al.  RAPL, a Rap1-binding molecule that mediates Rap1-induced adhesion through spatial regulation of LFA-1 , 2003, Nature Immunology.

[64]  M. Shimaoka,et al.  Stabilizing the integrin αM inserted domain in alternative conformations with a range of engineered disulfide bonds , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[65]  Junichi Takagi,et al.  Computational design of an integrin I domain stabilized in the open high affinity conformation , 2000, Nature Structural Biology.

[66]  M. Arnaout,et al.  An Isoleucine-based Allosteric Switch Controls Affinity and Shape Shifting in Integrin CD11b A-domain* , 2000, The Journal of Biological Chemistry.

[67]  T. Shimomura,et al.  Thrombospondin-bound Integrin-associated Protein (CD47) Physically and Functionally Modifies Integrin αIIbβ3 by Its Extracellular Domain* , 2003, Journal of Biological Chemistry.

[68]  Eric R. Prossnitz,et al.  Real Time Analysis of the Affinity Regulation of α4-Integrin , 2001, The Journal of Biological Chemistry.

[69]  N. Green,et al.  Electron microscopy and structural model of human fibronectin receptor. , 1988, The EMBO journal.

[70]  M. Humphries,et al.  An unraveling tale of how integrins are activated from within. , 2003, Trends in pharmacological sciences.

[71]  D. Jeanfavre,et al.  Molecular regulation of the interaction between leukocyte function-associated antigen-1 and soluble ICAM-1 by divalent metal cations. , 1998, Journal of immunology.

[72]  N. Kieffer,et al.  Green fluorescent protein (GFP) tagged to the cytoplasmic tail of αIIb or β3 allows the expression of a fully functional integrin αIIbβ3: effect of β3GFP on αIIbβ3 ligand binding , 2001 .

[73]  Michael Loran Dustin,et al.  Regulation of locomotion and cell-cell contact area by the LFA-1 and ICAM-1 adhesion receptors. , 1992, Journal of immunology.

[74]  G. Bazzoni,et al.  Are changes in integrin affinity and conformation overemphasized? , 1998, Trends in biochemical sciences.

[75]  K. Burridge,et al.  RhoA and ROCK Promote Migration by Limiting Membrane Protrusions* , 2003, The Journal of Biological Chemistry.

[76]  R. Liddington,et al.  Structural determinants of integrin recognition by talin. , 2003, Molecular cell.

[77]  W. Huber,et al.  Determination of kinetic constants for the interaction between the platelet glycoprotein IIb-IIIa and fibrinogen by means of surface plasmon resonance. , 1995, European journal of biochemistry.

[78]  J. Harlan,et al.  Requirement for RhoA Kinase Activation in Leukocyte De-Adhesion1 , 2002, The Journal of Immunology.

[79]  F. Maxfield,et al.  Ca2+- and calcineurin-dependent recycling of an integrin to the front of migrating neutrophils , 1995, Nature.

[80]  R. Liddington,et al.  Two conformations of the integrin A-domain (I-domain): a pathway for activation? , 1995, Structure.

[81]  Jun Qin,et al.  A Structural Mechanism of Integrin αIIbβ3 “Inside-Out” Activation as Regulated by Its Cytoplasmic Face , 2002, Cell.

[82]  T. Springer,et al.  The critical cytoplasmic regions of the αL/β2 integrin in Rap1-induced adhesion and migration , 2003 .

[83]  M. Yeager,et al.  Three-dimensional model of the human platelet integrin αIIbβ3 based on electron cryomicroscopy and x-ray crystallography , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[84]  V. Moy,et al.  Direct evidence for two affinity states for lymphocyte function-associated antigen 1 on activated T cells. , 1993, The Journal of biological chemistry.

[85]  Joanna C. Porter,et al.  LFA-1-induced T cell migration on ICAM-1 involves regulation of MLCK-mediated attachment and ROCK-dependent detachment , 2003, Journal of Cell Science.

[86]  R. Alon,et al.  Chemokine Stimulation of Lymphocyte α4Integrin Avidity but Not of Leukocyte Function-associated Antigen-1 Avidity to Endothelial Ligands under Shear Flow Requires Cholesterol Membrane Rafts* , 2002, The Journal of Biological Chemistry.