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ADHESION MOLECULES ³

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-cadherin	Intraepithelial T-lymphocytes (IEL) (Intestinal)
α11		Uterus, Heart, Skeletal muscle, Smooth muscle containing tissues

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 Homophilic: Neural specific Ig Cell Adhesion molecules (IgCAMs) Heterophilic: Systemic IgCAMs Adhesion Sites: Ig fold(s) domains (Distal); Fibronectin type III (Fn3) domains Inhibited by sialylation Ca++ independent Functions Neurite outgrowth Myelination Firm adhesion of leukocytes Via LFA/ICAM-1 & VLA-4/VCAM-1
NEURAL SPECIFIC IgCAMS
Molecule	Ligands	Distribution Disease
Abundant in CNS
CHL1		CNS: Axon pathways
L1CAM	Axonin	Neural: Wide CNS distribution SPG1
Neurofascin	Ankyrin-G SCN1B; SCN3B	Neural; Synapse NEDCPMD
NrCAM	Ig Superfamily	Neural: Ventral midline   Neurons & Glia Motor Neuropathy;   Neurodevelopmental Δ
Other Neural Ig-CAMs
Adhesion molecule on glia (AMOG; ATP1B2)		Glial Neural migration
Contactin-1 (CNTN1)	NOTCH1	Neural; NMJs Congenital myopathy, Lethal
Myelin-associated glycoprotein (MAG)	MAG	Myelin Demyelinating Neuropathy
Myelin-oligodendrocyte   glycoprotein (MOG)		Myelin; Oligodendrocytes Cytoplasmic membranes
NCAM-1 (CD56)	NCAM-1 via polysialic acid Modulated by   Sialyltransferase X   Polysialyltransferase	Muscle fibers, Atrophic Neural cells Schwann cells, non-myelinating Satellite cells Nerve pathology
NCAM-2		Neural
OBCAM	Opioids (μ); Acidic lipids	Brain
P0 protein	P0	Myelin
PMP-22 protein	PMP-22	Myelin
CADM1 (SynCAM1; Necl2)	Ig Superfamily	Pre- & Postsynaptic; DRG Induces presynaptic differentiation
CADM2 (SynCAM2; Necl3)	Necls & Nectins	Myelinated axons Binds to oligodendrocytes
CADM3 (SynCAM3; Necl1)	Necl1, Necl2, Necl4	PNS myelinated axons; DRG; CNS neurons
CADM4 (SynCAM4; Necl4)	Necl1	Myelinating Schwann cells; DRG Binds to CADM3 on axons
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 General Evolutionarily ancient Widely expressed Extracellular domain 5 Tandem repeats Each repeat comprises 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 (CDH1) Muscle IM-VAMP (IBM): Increased expression in muscle Increased with muscle fiber regeneration Blepharocheilodontic syndrome 1 Tumor malignancy & invasion: Reduction correlates with Gynecologic malignancies Point mutations in tumor cells Somatic loss of heterozygosity common Gastric malignancies Susceptibility to Listeria monocytogenes infection Cadherin M (CDH15) Myogenesis MRD3 Cadherin N (CDH2) Role in establishment of left-right asymmetry ARVD 14 ACOGS Cadherin P (CDH3) Congenital hypotrichosis + Juvenile macular dystrophy Ectodermal dysplasia, Ectrodactyly + Macular dystrophy Cadherin VE: Expression reduced in angiosarcomas Cadherin 23 Deafness: Age-related & Non-syndromic (DFN12) Usher syndrome Protocaderin 19 : Epilepsy, female (DEE9) Catenin α-3 (CTNNA3): ARVD13 Catenin β1 (Cadherin-associated protein) Mutations in malignancies NEDSDV Desmoglein 2: Cardiomyopathies (CMD1BB; ARVD10) Desmoglein 3: Antibody target in pemphigus
Molecule	Ligands	Distribution
Cadherin E (1)	H	Epithelial
Cadherin N (2)	O	Neural, Muscle
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