Integrin‐dependent pathologies

Cell adhesion and migration are essential for embryonic development, tissue regeneration, and immune defence. The physical link between the extracellular substrate and the actin cytoskeleton is mediated by receptors of the integrin family and a large set of adaptor proteins. During cell migration this physical link is dynamically modified, allowing the cell to sense and adapt to the microenvironment. This includes the formation of integrin clusters at the cell front, their stabilization in the cell body and subsequent disassembly of these clusters at the rear of the cell. The modulation of the adhesion strength of the cell to the substrate is regulated by the affinity switch of integrin molecules and increased avidity through clustering of integrins. Here we explain how integrins mediate cell migration and how genetic defects of integrins and their adaptors lead to cellular dysfunction and generate pathological situations. Copyright © 2003 John Wiley & Sons, Ltd.

[1]  R. Goldman,et al.  Microfilament‐dependent movement of the β3 integrin subunit within focal contacts of endothelial cells , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  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.

[3]  Jyrki Heino,et al.  Expression of α7β1 Integrin Splicing Variants during Skeletal Muscle Regeneration , 2002 .

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

[5]  L. Parise Integrin αIIbβ3 signaling in platelet adhesion and aggregation , 1999 .

[6]  S. Winder,et al.  Muscular dystrophies, the cytoskeleton and cell adhesion , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[7]  B. Geiger,et al.  Assembly and mechanosensory function of focal contacts. , 2001, Current opinion in cell biology.

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

[9]  C. Damsky,et al.  Requirement of the NPXY motif in the integrin beta 3 subunit cytoplasmic tail for melanoma cell migration in vitro and in vivo , 1995, The Journal of cell biology.

[10]  Kurt I. Anderson,et al.  Contact dynamics during keratocyte motility , 2000, Current Biology.

[11]  Micah Dembo,et al.  Separation of Propulsive and Adhesive Traction Stresses in Locomoting Keratocytes , 1999, The Journal of cell biology.

[12]  A. Ridley Rho GTPases and cell migration. , 2001, Journal of cell science.

[13]  Richard O Hynes,et al.  Integrins Bidirectional, Allosteric Signaling Machines , 2002, Cell.

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

[15]  F. Watt,et al.  A tumor-associated β1 integrin mutation that abrogates epithelial differentiation control , 2003, The Journal of cell biology.

[16]  L. Addadi,et al.  Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates , 2001, Nature Cell Biology.

[17]  F. Ross,et al.  Superactivation of integrin alphavbeta3 by low antagonist concentrations. , 2001, Journal of cell science.

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

[19]  D. Cheresh,et al.  Role of alpha v integrins during angiogenesis. , 2000, Cancer journal.

[20]  J. Qin,et al.  A structural mechanism of integrin alpha(IIb)beta(3) "inside-out" activation as regulated by its cytoplasmic face. , 2002, Cell.

[21]  G L Johnson,et al.  Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[22]  L. Smilenov,et al.  Focal adhesion motility revealed in stationary fibroblasts. , 1999, Science.

[23]  D. Cheresh,et al.  Requirement of vascular integrin alpha v beta 3 for angiogenesis. , 1994, Science.

[24]  R. V. van Lier,et al.  Leukocyte adhesion deficiency type 1 (LAD-1)/variant. A novel immunodeficiency syndrome characterized by dysfunctional beta2 integrins. , 1997, The Journal of clinical investigation.

[25]  J. Colón,et al.  Autoantibodies to Human α6 Integrin in Patients with Oral Pemphigoid , 2001 .

[26]  C. Nobes,et al.  Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia , 1995, Cell.

[27]  J W Smith,et al.  Integrin activation controls metastasis in human breast cancer. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  P. Nurden,et al.  A point mutation in the cysteine-rich domain of glycoprotein (GP) IIIa results in the expression of a GPIIb-IIIa (alphaIIbbeta3) integrin receptor locked in a high-affinity state and a Glanzmann thrombasthenia-like phenotype. , 2001, Blood.

[29]  Nigel Klein,et al.  A novel form of integrin dysfunction involving β1, β2, and β3 integrins , 2003 .

[30]  Jyrki Heino,et al.  Expression of alpha7beta1 integrin splicing variants during skeletal muscle regeneration. , 2002, The American journal of pathology.

[31]  Christoph Ballestrem,et al.  Marching at the front and dragging behind , 2001, The Journal of cell biology.

[32]  D. Cheresh,et al.  Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. , 1994, Cell.

[33]  R. Aster,et al.  The human platelet alloantigens, PlA1 and PlA2, are associated with a leucine33/proline33 amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing. , 1989, The Journal of clinical investigation.

[34]  T. N. Campbell,et al.  Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[35]  E. Hoffman,et al.  Integrin α7β1 in Muscular Dystrophy/Myopathy of Unknown Etiology , 2002 .

[36]  M. Järvinen,et al.  Integrin and dystrophin associated adhesion protein complexes during regeneration of shearing-type muscle injury , 2000, Neuromuscular Disorders.

[37]  J. Weiss,et al.  A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. , 1996, The New England journal of medicine.

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

[39]  R. Fässler,et al.  Absence of integrin alpha 7 causes a novel form of muscular dystrophy. , 1997, Nature genetics.

[40]  B. Imhof,et al.  Actin, microtubules and focal adhesion dynamics during cell migration. , 2003, The international journal of biochemistry & cell biology.

[41]  E. Hoffman,et al.  Mutations in the integrin alpha7 gene cause congenital myopathy. , 1998, Nature genetics.

[42]  J. Uitto,et al.  Homozygous alpha6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia. , 1997, Human molecular genetics.

[43]  M. Schwartz,et al.  Rac recruits high-affinity integrin alphavbeta3 to lamellipodia in endothelial cell migration. , 2001, Nature cell biology.

[44]  P A Bates,et al.  Genetic analysis of integrin function in man: LAD-1 and other syndromes. , 2000, Matrix biology : journal of the International Society for Matrix Biology.

[45]  K. Jacobson,et al.  The composition and dynamics of cell-substratum adhesions in locomoting fish keratocytes. , 1997, Journal of cell science.

[46]  D. Vestweber,et al.  Leukocyte Adhesion Deficiency II: Therapy and Genetic Defect , 2002, Cells Tissues Organs.

[47]  R. Adams,et al.  A novel syndrome of variant leukocyte adhesion deficiency involving defects in adhesion mediated by beta1 and beta2 integrins. , 2001, Blood.

[48]  K. Rottner,et al.  Interplay between Rac and Rho in the control of substrate contact dynamics , 1999, Current Biology.

[49]  Beat Imhof,et al.  The inner lives of focal adhesions. , 2002, Trends in cell biology.

[50]  Y. Tomiyama Glanzmann thrombasthenia: integrin alpha IIb beta 3 deficiency. , 2000, International journal of hematology.

[51]  L. Parise Integrin alpha(IIb)beta(3) signaling in platelet adhesion and aggregation. , 1999, Current opinion in cell biology.

[52]  M. Jonkman,et al.  Deletion of a cytoplasmic domain of integrin beta4 causes epidermolysis bullosa simplex. , 2002, The Journal of investigative dermatology.

[53]  N. Kieffer,et al.  Probing conformational changes in the I-like domain and the cysteine-rich repeat of human beta 3 integrins following disulfide bond disruption by cysteine mutations: identification of cysteine 598 involved in alphaIIbbeta3 activation. , 2001, The Journal of biological chemistry.

[54]  T. Springer,et al.  Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins. , 1987, Annual review of medicine.

[55]  D. Mohanty,et al.  Glanzmann's thrombasthenia: updated , 2002, Platelets.

[56]  E. Zamir,et al.  Molecular complexity and dynamics of cell-matrix adhesions. , 2001, Journal of cell science.

[57]  P. Bray,et al.  The Pl(A2) polymorphism of integrin beta(3) enhances outside-in signaling and adhesive functions. , 2000, The Journal of clinical investigation.

[58]  D. Staunton,et al.  A novel genetic leukocyte adhesion deficiency in subsecond triggering of integrin avidity by endothelial chemokines results in impaired leukocyte arrest on vascular endothelium under shear flow. , 2003, Blood.

[59]  B. Imhof,et al.  Actin dynamics in living mammalian cells. , 1998, Journal of cell science.

[60]  Stephen J. Kaufman,et al.  Enhanced Expression of the α7β1 Integrin Reduces Muscular Dystrophy and Restores Viability in Dystrophic Mice , 2001, The Journal of cell biology.

[61]  D. Cheresh,et al.  Integrin α v β 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels , 1994, Cell.

[62]  S. Kumari,et al.  Autoantibodies to human alpha6 integrin in patients with oral pemphigoid. , 2001, Journal of dental research.

[63]  Klemens Rottner,et al.  The lamellipodium: where motility begins. , 2002, Trends in cell biology.

[64]  Robert C. Liddington,et al.  Faculty Opinions recommendation of Crystal structure of the extracellular segment of integrin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand. , 2002 .

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

[66]  J. Weissenbach,et al.  Mutations in the laminin α2–chain gene (LAMA2) cause merosin–deficient congenital muscular dystrophy , 1995, Nature Genetics.

[67]  D. Elder,et al.  Integrin distribution in malignant melanoma: association of the beta 3 subunit with tumor progression. , 1990, Cancer research.

[68]  Benjamin Geiger,et al.  Focal Contacts as Mechanosensors Externally Applied Local Mechanical Force Induces Growth of Focal Contacts by an Mdia1-Dependent and Rock-Independent Mechanism , 2001 .

[69]  M. Margaglione,et al.  Glanzmann’s Thrombasthenia: Identification of 19 New Mutations in 30 Patients , 2002, Thrombosis and Haemostasis.

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

[71]  J. Weissenbach,et al.  Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. , 1995, Nature genetics.

[72]  T. Springer,et al.  The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency: their quantitative definition and relation to leukocyte dysfunction and clinical features. , 1985, The Journal of infectious diseases.

[73]  J. Uitto,et al.  Mutation analysis and molecular genetics of epidermolysis bullosa. , 1999, Matrix biology : journal of the International Society for Matrix Biology.

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

[75]  P. Bray,et al.  The PlA2 polymorphism of integrin β3 enhances outside-in signaling and adhesive functions , 2000 .

[76]  J. Uitto,et al.  Novel ITGB4 mutations in lethal and nonlethal variants of epidermolysis bullosa with pyloric atresia: missense versus nonsense. , 1998, American journal of human genetics.

[77]  B. Yaspan,et al.  Calpain cleavage promotes talin binding to the beta 3 integrin cytoplasmic domain. , 2001, The Journal of biological chemistry.