Diagrams & Tables: Cell Adhesion Molecules

Adhesion Molecules, CAMs: Cell adhesion relies upon specialized transmembrane adhesion proteins that usually extend from the intracellular space to the extracellular space where they bind ligands in other cell membranes or in the extracellular matrix. Some signaling molecules act as adhesion receptors and cluster in focal adhesions upon ligand binding. adapted from 1, 2.

Binding:	Cell-to-Cell	Cell-to-ECM
calcium dependent, or cation modulated	cadherins, selectins integrins	integrins
calcium independent	Ig superfamily
transient/rolling	E-selectins: (initial PMN-endothelial adhesion) L-selectins: constitutive trafficking of lymphocytes through secondary lymphoid organs (leukocyte-endothelium, or leukocyte-leukocyte). VCAM [r] & MAdCAM
tighter		integrins
constitutive, tightest	Ig superfamily desmogleins & desmocollins

Ligand type
heterophilic	selectins to carbohydrates Ig superfamily to integrins, ICAM-1 to selectins Ig superfamily to different Ig superfamily, systemic IgCAMs cadherins via catenins to cytoskeleton integrins
homophilic	Ig superfamily to Ig superfamily (neural IgCAMs) cadherins to cadherins
Anchor
actin cytoskeleton	Cadherins N; P; R; B; E
desmosome/tight junction	Desmogleins & desmocollins interact with intermediate filaments ( tight junctions).
extracellular ligands	integrins
Tissue type
immune system signaling	FAS ligand, TNF receptor family, CD28 & B7, CD40, CD31 (platelet endothelial cell adhesion molecule-1 [PECAM-1]/endothelial cell adhesion molecule [endoCAM][r])
muscle	Cadherins-M
nervous	Cadherins-N, neural IgCAMS
vascular	L-selectins leukocytes, E-selectins endothelial cells; P-selectins platelets and endothelial cells. integrins
widely expressed	Cadherins
Function/Malfunction
inflammation	P-selectins
malignancy	Cadherin-E-catenin
migration, motility	selectins AMOG - neural migration CD-31, or PECAM-1 Catenins probably trigger changes in cell shape and motility with signals via Rho small GTPases. α4β1; α4β7; Fibronectin;VCAM-1; MAdCAM-1; TSP-1: T-cell transendothelial migration
signaling	cadherins interact with receptor tyrosine kinases (RTKs). L1 & NCAM (with src PTKs)[1] CD2, LFA-3 or CD4, CD8. focal adhesion complex (Paxillin adaptor protein) CEACAM1 integrins
tight-junctions	desmogleins & desmocollins
tissue integrity (solid)	cadherins integrins

Cadherins Calcium dependent adhesion molecules
Structure	Single-pass transmembrane glycoprotein ~ 700-750 residues, often dimers. Anchor is cytoplasmic carboxy-terminal domain of transmembrane segment. Intracellular cytoplasmic domain binds intracellular domain binds to specific proteins, catenins, which then bind to actin cytoskeleton. Extracellular domain ~ 100 amino acid residues, calcium binding sites, homophilic binding (CDH-CDH) may use His-Ala-Val sequence, has 5 tandem repeats, each comprising sandwich of β sheets.
Location/Ligand	Evolutionarily ancient; widely expressed. Almost all vertebrate cells express one or more cadherins. Cadherins N; P; R; B; E are interactive with actin cytoskeleton. Cadherin type: intracellular → cytoplasmic filaments. Cadherins-E,-P: catenins, alpha actinin → actin. Desmosome associated: Desmogleins & Desmocollins interact with intermediate filaments ( tight junctions). Desmosomal: desmoplakins I, II, Plakoglobin, keratin → desmin. N-cadherin: catenins, alpha actinin, vinculin → actin. Protocadherins display homology to cadherins, have extracellular, but not intracellular, domains
Function	Cadherin-E (1): reduction correlates with malignancy & tumor invasion. Cadherin-M: Myogenesis Cadherin-N: Role in establishment of left-right asymmetry Cadherin- P (3): Congenital hypotrichosis with juvenile macular dystrophy Cadhein VE: Expression reduced in human angiosarcomas Cadherin 23: Deafness, Age-related & non-syndromic; Usher syndrome Catenin β1 (Cadherin-associated protein): Mutations in malignancies Desmoglein 3: Antibody target in pemphigus
Ig superfamily Non-Calcium dependent Cell to Cell binding
Structure	Transmembrane segment & cytoplasmic tail. Adhesion sites - 1 or more repeats of Ig fold of 60 to 100 amino acids. Ig domain has no somatic hypermutations. Sandwiches of 2 β sheets adherent by hydrophobic interactions. Constitutive or long-term up-regulated
Location/Ligand	Evolutionarily ancient; widely expressed. 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. Ligands of neural IgCAMS: Ig superfamily, Axonin, MAG, NCAM-1, opiods, Po, PMP-22 Ligands of systemic IgCAMs: CD6; CD166;NgCAM; 35 kD protein, sialylated glycoproteins, LCA (CD45), Hyaluronin; Ankyrin; Fibronectin; MIP1, βOsteopontin, αLβ2; LFA-1, αLβ2 (LFA-1), αLβ2, LFA-3, LFA-2, α4β7; L-selectin, CD31; αvβ3, α4β1; α4β7
Function	Neurite outgrowth, myelination, firm adhesion of leukocytes via LFA/ICAM-1 & VLA-4/VCAM-1
Integrins Cell to Matrix Binding & Cell to Cell binding through special Integrins
Structure	Heterodimeric transmembrane glycoproteins. 16 α chains & 8 β chains, heterodimers with 1 α chain & 1 β chain, binding site on β subunit, α subunit may mediate specificity of ligand binding Subunits: large (α) 120-170 kDa, small (β) 90-100 kDa.
Location/Ligand	Binding sites for divalent cations Mg2+ and Ca2+ (necessary for adhesive function). Binding often occurs after weaker, rolling selectin binding. Low affinity binding to extracellular ligands - often single specific IgCAM; ICAM-1; ICAM-2; ICAM-3; VCAM-1; MAdCAM-1; TSP-1; or subset of extracellular matrix molecules (Fibronectin; Laminins). → Intracellular ligands: Talin; α-actinin. Intracellular ligands then linked to structural proteins (Vinculin; Actin microfilaments) and to signaling pathways partly via pp125FAK , a focal adhesion-associated kinase (FAK)
Function	Mediate direct cell to cell recognition and interactions, attach cells to extracellular matrix proteins of the basement membrane or to ligands on other cells. Cause receptor clustering, autophosphorylation of tyrosine residues. Loss of integrin interaction may induce apoptosis. β1 integrin required in muscle for innervation by motor axons
Selectins Cell to Cell Surface Carbohydrate Binding Proteins : Calcium dependent
Structure	Transient, single transmembrane polypeptide (lectins), small cytoplasmic tail, N-terminal is homologous to Ca++-dependent lectins, EGF motif, 62 aa repeats show homology to complement regulatory proteins Heterophilic binding to oligosaccharides on another cell (incl. neutrophils) in presence of calcium.
Location/Ligand	L-leukocytes; E-endothelial cells; P-platelets and endothelial cells. Vertebrate blood, vascular, immune, heart, muscle, uterus, nervous system - adhesion glycoproteins bound to sialated glycans - Ca++ dependent adhesion of amino-terminal domain. Rapidly down-regulated
Function	Leukocyte-endothelial interactions. E-selectin mediates initial PMN adhesion to endothelial cells. L-selectins -constitutive trafficking of lymphocytes through secondary lymphoid organs. Local chemical mediators at the site of inflammation signal the endothelial cells to express P-selectins, which allow the initial binding of white blood cells to endothelial cells -weak binding, so WBC roll along endothelium until bound more strongly by integrins.