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ADHESION MOLECULES3

Cadherins
Cell movement
  Cell migration
  Leukocyte emigration
Connexins
Dystroglycan-Sarcoglycan
Gap junctions
Immunoglobulin superfamily
  General principles
  Neural specific
  Systemic
Integrins
Proteoglycans
Selectins
Other


SELECTINS
General principles
  • Expressed: Only in vertebrates; In circulatory cells (Endothelium & Blood cells)
  • Single transmembrane polypeptide
  • Structure
    • N-terminal: Homologous to Ca++-dependent lectins
    • EGF motif
    • 62 amino acid repeats: Homology to complement regulatory proteins
    • Transmembrane region
    • Cytoplasmic tail
  • Induced, then rapidly downregulated
  • Adhesion
    • Transient
    • Architecture
      • Binding site: Amino-terminal domain
      • Connecting arm: Contains EGF-like domain & peptide repeats
    • Ca++ dependent
    • Ligands: Sialated glycans (Similar pattern of binding to sialoadhesins)
  • Functions
    • Slow intravascular leukocytes before transendothelial migration
    • E-selectin: Mediates initial PMN adhesion to endothelial cells
    • Adhesion is rolling, not firm
    • Firm adhesion via LFA/ICAM-1 & VLA-4/VCAM-1
Molecule Ligands Distribution
L-selectin (CD62L) Sulfated:
GlyCAM-1 ; CD34 ; MAdCAM-1
Leukocytes
  (Homing receptor)
E-selectin (CD62e) Tetrasaccharides: Sialyl-Lewisx; Sialyl-Lewisa
Cutaneous lymphocyte-associated antigen
Endothelial cells
P-selectin (CD62P) Tetrasaccharides: Sialyl-Lewisx
P-selectin glycoprotein ligand-1
Endothelial cells
Platelets

INTEGRINS
General principles
  • Family
    • 16 α chains & 8 β chains
    • Transmembrane adhesion molecules
    • Usually in low affinity conformation
    • Activated by
      • Conformational changes: Induced by ligand binding or intracellular processes
      • ? Expression at transcriptional level
  • Heterodimers with 1 α chain & 1 β chain
    • Both subunits transmembrane
    • Non-covalently bound
    • 22 different heterodimers identified
  • Exist in variable activation states
  • Adhesion
    • Binding site: On β subunit
    • Modified by metal binding to α subunit
      • α subunit may mediate specificity of ligand binding
    • Binding also influenced by divalent cations
    • Often occurs after selectin binding
    • Extracellular ligands: Binding is low affinity
      • Often single specific IgCAM
      • Subset of extracellular matrix molecules: Fibronectin; Laminins
    • Intracellular ligands: Talin; α-actinin
    • Intracellular ligands then linked to
      • Structural proteins: Vinculin; Actin microfilaments
      • Signaling pathways
        • Partly via pp125FAK , a focal adhesion-associated kinase
    • Effects of extracellular ligand binding
      • Receptor clustering
      • Autophosphorylation of tyrosine residues
      • Loss of integrin interaction may induce apoptosis
  • NMJ formation: β1 integrin required in muscle for innervation by motor axons
Molecule Ligands Distribution
α1β1 Laminin; Collagen
Tenascin, common form
NK, B & Activated T cells; Fibroblasts; Glial
Perineurium; Schwann cells; Endothelial
α2β1 Laminin; Collagen NK, B & Activated T cells; Platelets
Endothelial; Fibroblasts; Epithelium
Astrocytes; Schwann cells; Ependymal
α3β1 Laminin; Collagen;
Fibronectin
Activated T cells; Thymocytes; Endothelium;
Fibroblasts; Epithelium; Astrocytes
α4β1 α4β1; α4β7; Fibronectin;
VCAM-1; MAdCAM-1; TSP-1
NK, B & T cells; Eosinophils; Endothelial;
Muscle; Fibroblasts; Neural-crest derived
Function: T cell Transendothelial migration
α5β1 Fibronectin; murine L1 Activated B & T cells; memory T-cells;
Thymocytes; Fibroblasts; Epithelium;
Platelets; Endothelial; Astrocytes
α-5 disease: Myopathy in Chimeric mouse
α6β1 Laminin Leukocytes; Thymocytes; Epithelial;
T cells (Memory & activated)
Glial; Fibroblasts; Endothelial
α-6 disease:
  Junctional epidermolysis bullosa
α7β1 Laminin Skeletal & cardiac muscle; Melanoma
α-7 disease: Congenital MD
Knockout ® Myopathy
α8β1
(CD-/CD29; VLA-8)
Fibronectin; Vitronectin
Tenascin, common form
Epithelium; Neurons; Oligodendroglia
α9β1
  Epithelium (airway); Muscle
αvβ1 Vitronectin; Fibronectin; Collagen
von Willebrand factor; Fibrinogen
Oligodendroglia
αLβ2
(LFA-1α; CD11a)
ICAM-1; ICAM-2; ICAM-3 Leukocytes; Thymocytes; Macrophages;
T cells; Microglia
β-2 disease:
   Leukocyte adhesion deficiency
αMβ2
(CD11b)
ICAM-1; Factor X;
iC3b; Fibrinogen
Myeloid; B cells (activated); NK cells;
Macrophages; Microglia; B leukemic cells
αXβ2
(CD11c)
iC3b; Fibrinogen Myeloid; Dendritic cells; B cells (activated);
Macrophages; Microglia; B leukemic cells
αIIbβ3 Fibronectin; Vitronectin;
von Willebrand's factor;
Thrombospondin
Platelets
β-3 disease:
   Glanzmann thrombasthenia, Type B
αvβ3
(CD51/CD61)
Fibronectin; Osteopontin;
von Willebrand's factor; PE-CAM-1
Vitronectin; Fibrinogen; human L1
Thrombospondin; Collagen
B cells (Activated); T cells (Activated & γδ);
Endothelium; Monocytes; Tumors;
Glia; Schwann cells; Endothelium
α6β4 Laminin Schwann cells; Perineurium;;
Endothelium; Epithelium; Fibroblasts
Not in immune cells
β-4 disease:
  Junctional epidermolysis bullosa
αvβ5
(CD51/CD-)
Vitronectin; Fibronectin;
Fibrinogen
Fibroblasts; Monocytes; Macrophages;
Epithelium; Oligodendroglia; Tumors
αvβ6 Fibronectin.
αvβ8 Fibronectin Oligodendroglia; Schwann cells;
Brain synapses
α4β7 Fibronectin;
VCAM-1; MAdCAM-1
NK, B & T cells
Not in neural cells
αIELβ7
(CD103)
E-cadherinIntraepithelial T-lymphocytes (IEL)
(Intestinal)
α11 Uterus, Heart, Skeletal muscle,
Smooth muscle containing tissues

Immunoglobulin  Superfamily
General features
  • Evolutionarily ancient; Widely expressed
  • Structure
    • 1 or more repeats of Ig fold of 60 to 100 amino acids: Form sites of adhesion
    • Ig domain: No somatic hypermutations
      • Sandwiches of 2 β sheets held together by hydrophobic interactions
    • Constitutive or long-term up-regulated
    • Anchor: Transmembrane segment & cytoplasmic tail
  • Interactions
  • Adhesion
    • Sites: Ig fold(s) domains (Distal); Fibronectin type III (Fn3) domains
    • Inhibited by sialylation
    • Ca++ independent
  • Functions
NEURAL SPECIFIC IgCAMS
Molecule Ligands Distribution
Adhesion molecule on glia
(AMOG)
Glial
Neural migration
Contactin-1
(CNTN1)
NOTCH1 Neural; NMJs
Lethal congenital myopathy
L1CAM  Axonin Neural
Myelin-associated glycoprotein
(MAG)
MAG Myelin
Neuropathy
Myelin-oligodendrocyte glycoprotein
(MOG)
  Myelin; Oligodendrocytes
Cytoplasmic membranes
NCAM-1 (CD56) NCAM-1 via polysialic acid
Modulated by
  Sialyltransferase X
  Polysialyltransferase
Neural cells
Satellite cells
NCAM-2   Neural
NrCAM Ig Superfamily Neural
OBCAM Opioids (μ); Acidic lipids Brain
P0 protein P0 Myelin
PMP-22 protein PMP-22 Myelin
Necl1 (SynCAM3; CADM3) Necl1, Necl2, Necl4 PNS myelinated axons; DRG;
CNS neurons
Necl2 (SynCAM1; CADM1) Ig Superfamily Pre- & Postsynaptic; DRG
Induces presynaptic differentiation
Necl3 (SynCAM2; CADM2) Necls & Nectins Myelinated axons
Binds to oligodendrocytes
Necl4 (SynCAM4; CADM4) Necl1 Myelinating Schwann cells; DRG
Binds to Necl1 on axons
Neurofascin Ankyrin-G ; SCN1B; SCN3B Neural; Synapse
MDGA1   Neural; Muscle
Radial migration of cortical neurons
SYSTEMIC IgCAMS
Molecule Ligands Distribution
ALCAM (CD166) CD6; CD166;
NgCAM; 35 kD protein
Neural; Leukocytes
Basigin (CD147) MMP1 Leukocytes; RBCs;
Platelets; Endothelial cells
BL-CAM (CD22) Sialylated glycoproteins
LCA (CD45)
B-Lymphocytes
CD44 Hyaluronin; Ankyrin;
Fibronectin; MIP1β
Osteopontin
Lymphocytes; Epithelial;
WM perivascular astrocytes
Glial tumors (malignant)
Metastases (CD44v splice variant)
ICAM-1 (CD54) αLβ2; LFA-1 Leukocytes; Endothelial cells;
Dendritic cells; Fibroblasts;
Epithelium; Synovial cells
Disease: Lys29Met mutation
  Susceptibility to cerebral malaria
ICAM-2 (CD102) αLβ2 (LFA-1) Endothelial cells;
Lymphocytes; Monocytes
ICAM-3 (CD50) αLβ2 Leukocytes
Lymphocyte function antigen-2
(LFA-2) (CD2)
LFA-3 Lymphocytes; Thymocytes
LFA-3 (CD 58) LFA-2 Leukocytes; Stroma
Endothelial cells
Astrocytoma
Major histocompatibility complex
(MHC) molecules
MAdCAM-1 α4β7; L-selectin Mucosal endothelial cells
PECAM (CD31) CD31; αvβ3 Leukocytes; Synovial cells
Endothelial cells
T-cell receptor
(C-region)
VCAM-1 α4β1; α4β7 Satellite cells
Monocytes; Synovial cells;
Activated endothelial cells

General principles
  • Evolutionarily ancient; Widely expressed
  • Extracellular domain: 5 Tandem repeats; Each comprising sandwich of β sheets
  • Binding
    • Homophilic: Via most distal cadherin repeats
    • Requires: Ca+; Specific intracytoplasmic binding
  • Often present as dimers
  • Anchor: Transmembrane segment; Cytoplasmic carboxy-terminal domain
  • Intracellular
    • Cytoplasmic domain binds catenins
    • Catenins then bind to actin cytoskeleton
  • Types
    • Interactive with actin cytoskeleton: Cadherins N; P; R; B; E
    • Desmosome associated: Desmogleins & Desmocollins
      • Interact with intermediate filaments
      • Location: In tight junctions

      From Swarthmore
    • Protocadherins
      • Homology to cadherins: Extracellular, but not intracellular, domains
  • Diseases & Functions
    • Cadherin E (1): Reduction correlates with tumor malignancy & invasion
      • Gynecologic malignancies
        • Point mutations in tumor cells
        • Somatic loss of heterozygosity common
      • Gastric malignancies
      • Susceptibility to Listeria monocytogenes infection
    • Cadherin M: Myogenesis
    • Cadherin N: Role in establishment of left-right asymmetry
    • Cadherin P (3): Congenital hypotrichosis with juvenile macular dystrophy
    • Cadherin VE: Expression reduced in human angiosarcomas
    • Cadherin 23: Deafness, Age-related & non-syndromic; Usher syndrome
    • Protocaderin 19 : Epilepsy, female
    • Catenin α-3 (CTNNA3): ARVD13
    • Catenin β1 (Cadherin-associated protein): Mutations in malignancies
      • Colon; Hepatoblastoma; Pilomatricoma; Ovarian (Endometrioid)
    • Desmoglein 2: Cardiomyopathies (CMD1BB; ARVD10)
    • Desmoglein 3: Antibody target in pemphigus
Molecule Ligands Distribution
Cadherin E (1) H Epithelial
Cadherin N (2) O Neural
Cadherin BR (12) M Brain
Cadherin P (3) O Placental
Cadherin R (4) P Retinal
Cadherin M (15) H Muscle, Activated satellite cells
Cadherin VE (5) (CD144) I Endothelial, Brain
Cadherin T & H (13) L Heart
Cadherin OB (11) I Osteoblast
Cadherin K (6) C Brain; Kidney
Cadherin 7
Cadherin 8 Brain
Cadherin KSP (16) Kidney
Cadherin LI (17) GI tract; Pancreas
Cadherin 18 CNS; Small cell lung cancer
Cadherin, Fibroblast 1 (19) Fibroblasts
Cadherin, Fibroblast 2 (20) Fibroblasts
Cadherin, Fibroblast 3 (21) Fibroblasts
Cadherin 23 Ear
Desmocollin 1 Skin
Desmocollin 2 Epithelium, Mucosa
Myocardium
Lymph nodes
Desmoglein 1 Epidermis, Tongue
Desmoglein 2 All
Desmoglein 3 Epidermis, Tongue
Antibody target in pemphigus
Protocadherin 1 ; 2 ; 3 ;
    7 ; 8 ; 9

OTHER ADHESION MOLECULES
Molecule Ligands Distribution
Agrin (Neural) MuSK; NCAM; Laminin
Heparin-binding proteins;
Heparan sulfate proteoglycan
Nerve
CD34 MAdCAM-1; L-selectin Immature lymph/myeloid
GlyCAM-1 L-selectin Lymph nodes
Oligodendrocyte-myelin glycoprotein
(OMGP)
Myelin; Oligodendrocytes



CELL MIGRATION


From Horwitz

Adhesion molecules involved in leukocyte
emigration from vessels during inflammation
2
Rolling Stopping
Aggregation &
  Shape Change
Migration through
  vessel wall



References
1. Can J Neurol Sci 1997;24:200-209
2. JAMA 1997;278:1804-1814
3. Trends in Genetics 1999;15:M33-M37


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6/27/2009