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.



calcium dependent, or

cation modulated

cadherins, selectins



calcium independent

Ig superfamily


E-selectins: (initial PMN-endothelial adhesion) L-selectins: constitutive trafficking of lymphocytes through secondary lymphoid organs (leukocyte-endothelium, or leukocyte-leukocyte).



constitutive, tightest

Ig superfamily

desmogleins & desmocollins

Ligand type


selectins to carbohydrates

Ig superfamily to integrins, ICAM-1 to selectins

Ig superfamily to different Ig superfamily, systemic IgCAMs

cadherins via catenins to cytoskeleton



Ig superfamily to Ig superfamily (neural IgCAMs)

cadherins to cadherins


actin cytoskeleton

Cadherins N; P; R; B; E

desmosome/tight junction Desmogleins & desmocollins interact with intermediate filaments ( tight junctions).
extracellular ligands


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])



Cadherins-N, neural IgCAMS


L-selectins leukocytes, E-selectins endothelial cells; P-selectins platelets and endothelial cells.


widely expressed







migration, motility


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

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)




desmogleins & desmocollins

tissue integrity (solid)




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.

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


Cell to Matrix Binding & Cell to Cell binding through special Integrins


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.


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


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.
 Cell signaling  Second Messengers  RTKs 

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Immune Cytokines

Cytokines are small proteins that regulate and mediate immunity, inflammation, and hematopoiesis. They are secreted de novo in response to immune stimuli, and usually act briefly, locally, at very low concentrations (the exception being endocrine action at distant cells). Cytokines bind to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter cellular activity (gene expression).

 Complement Receptors  Fc receptors  Immunoglobulins  Interferons  Scavenger Receptors  Toll-like Receptors  Cell Adhesion Molecules  Cell signaling  Receptor Tyrosine Kinases (RTKs)  Receptor Signal Transduction  Second Messengers

Producer cell/tissue
Target cell

Granulocyte/Monocyte Colony Stimulating Factor (CSF)

endothelium, macrophages

growth and differentiation of neutrophils
growth and differentiation of monocytes and dendritic cells
thymic epithelial cells (TEC), PMN, chondrocytes, glomerular mesangial cells, Ishikawa cells lymphohematopoietic growth and differentiation of monocytes, enhances expression of differentiation- antigens and stimulates chemotactic, phagocytic, and cytotoxic activities of monocytes


IL-1a IL-1b
maturation and proliferation
inflammation, acute phase response, fever


cell growth, proliferation, activation,

synthesis of antibodies


(multi-CSF) hematopoietin

growth and differentiation
growth, and histamine release


proliferation and differentiation IgG1 and IgE synthesis
MHC Class II
proliferation and differentiation IgA synthesis
IL-6 receptor has two subunits - an alpha subunit that produces ligand specificity, and a p130 receptor subunit. Signals through JAK kinases and activation of Ras-mediated signaling
differentiation into plasma cells → secretion of antibodies
costimulator of T cells
acute phase response

neurons, osteoblasts

neuronal differentiation, bone loss
differentiation into progenitor B and T cells
macrophages endothelial cells
inhibition of macrophage function, cytokine production
differentiation into CTL (with IL-2)

Interferons  Interferons

viral replication MHC I expression
viral replication MHC I expression
viral replication
MHC expression
Ig class switch to IgG2a
pathogen elimination

Macrophage Inflammatory Proteins


Transforming Growth Factor

activated macrophages
IL-1 synthesis
IgA synthesis

Tumor Necrosis Factor

CAM and cytokine expression
cell death
lymphotoxin-α (LT)
phagocytosis, with no production; activation effector cells to infection sites, leukocyte adhesion to endothelial cells, peripheral lymphoid organogenesis, stimulation of B cells

cell death through inhibition of tumor angiogenesis

 Cell Adhesion Molecules  Cell signaling  Complement Receptors  Fc receptors  Immune Cytokines  Immunoglobulins  Receptor Tyrosine Kinases (RTKs)  Receptor Signal Transduction  Second Messengers  Scavenger Receptors  Toll-like Receptors

Receptor Signal Transduction

Protein receptors bind specific ligands as the initial step in signal transduction to participate in cellular signaling, gene regulation, cellular proliferation, cellular differentiation, or regulation of cellular metabolic processes. A ligand is any molecule that binds reversibly to a specific site on a protein, and can be nucleic acids, polysaccharides, lipids, hormones, neurotransmitters, amino acids, peptides, polypeptides, or another proteins. Ligand-protein binding may be simple, allosteric, or competitive. Metabotropic receptors are coupled to G proteins, acting through various secondary pathways involving ion channels, enzymes such as adenylyl (adenylate) cyclases, and phospolipases, or PDZ domains. Ionotropic receptors are ligand-activated ion channels that permit entry of ions when the central pore is open.

Plasma membrane receptors

Receptor family [iuphar]



cytokine receptors = G- protein Cytokines of immune response Metabotropic receptor
Guanine nucleotide-binding protein-coupled receptors (GPCRs) of GPCR families

Neurotransmitters : acetylcholine, dopamine, epinephrine, GABA, glutamate, serotonin. Nucleoside : adenosine. Hormones : angiotensin, cholecystokinin, glucagon, secretin, somatostatin. Cytokines chemokines. Histamines - H1,2,3,4. Cannabinoids and Opioids. Sensory stimuli - olfaction, vision. Calcium.

Metabotropic / sensory
Guanylyl cyclase receptors ANP and natriuretic peptides (GC-A & GC-B), Guanylin (GC-C) Metabotropic. Guanylyl cyclases convert GTP to the second messenger, cGMP.
neurotransmitter ion channels Neurotransmitters: acetylcholine, GABA, glutamate, glycine, serotonin Ionotropic
receptor tyrosine kinases (RTKs): EGFR, Tie receptors, Eph RTKs, IGF-1 growth factors, insulin, erythropoietin, cytokines Metabotropic
TGF-β receptors; activin, BMP: associated with serine/threonine kinases: MAPK cascade; phosphoinositol kinase-related kinase (PIKK) family - mTOR (FRAP1), ATM, ATR, DNA-PK growth factors, transforming growth factor β, mitogens, leucine, insulin, nutrients → Ras, phosphatidylinositol-3-OH kinase
TNF receptors FasL (pro-apoptotic protein induced by DNA damage) Fas-associated death domain protein (FADD) regulation of apoptosis.

Intracellular receptors

Ligand to cytoplasmic receptor


steroid hormones: bind transcription factor receptors. Type I HREs: sex hormones, glucocorticoids, mineralocorticoids. Type II nuclear receptors: thyroid hormone, vitamins A & D, retinoid. Orphan receptors. alter gene expression
inositol trisphosphate (IP3) release of stored second messenger calcium ions
sigma1: neuroactive steroids (neurosteroids) allosteric modulators of neurotransmitter receptors: DHEA, PREG, PROG, PROG-R alter neuronal excitability through interaction with neurotransmitter-gated ion channels

Signaling pathways

mitogen-activated protein kinase (MAPK)/Ras signaling cascades
phosphatidyl inositol-3-kinase (PI3K)/AKT
protein kinase C

Specific genes encoding receptors




FAS gene TNFRSF6 - tumor necrosis receptor 6 apoptosis

Second Messengers

The membrane receptors that induce second messengers are GPCRs of GPCR families. Stimulation of the guanine nucleotide-binding protein-coupled receptors leads to signal transduction of sensory, hormonal, or photic stimuli into regulation of effector enzymes and ion channels. Signal transduction is accomplished through the coupling of G-proteins, via second messengers, to various secondary pathways involving ion channels, adenylyl cyclases, and phospholipases. Further, GPCRs may also couple to other proteins, such as those containing PDZ domains. GPCRs are diverse and of ancient evolutionary lineage, and are found in fungi, plants, and animals.




Acts on


Adrenaline, glucagon, luteinizing hormone (LH), parathyroid hormone (PTH), adrenocorticotropic hormone (ACTH) adenylyl (adenylate) cyclases

cAMP-dependent protein kinase, (PKA),

gene transcription


Photic response of retinal rods (rhodopsin), nitric oxide (NO), atrial natriuretic peptide (ANP), guanyl cyclase protein kinase G (PKG)

diacylglycerol (DAG)

growth factors phospholipase C-gamma protein kinase C (calcium dependent)

Inositol-1,4,5-trisphosphate (IP3)

growth factors phospholipase C-gamma

protein kinase C (calcium dependent)

Ca2+ ions

Voltage-gated channels – after depolarization by an action potential; receptor-operated ion channels in post-synaptic membranes, which open upon nt-binding; GPCRs muscle contraction, neurotransmitter release at neuronal synapses (LTP, LTD), secretion of hormones, apoptosis, cell adhesion to extracellular matrix, T/B cell activation neurotransmitter release at neuronal synapses, secretion of hormones, apoptosis, cell adhesion to extracellular matrix, activation of T and B cells
 Cell signaling  Receptor Tyrosine Kinases(RTK)  Second Messengers  Phosphate-handling Enzymes  · adenylyl (adenylate) cyclase · calcium ion · calcium ions · cAMP-dependent protein kinase · CDKs · cyclin-dependent kinases · DAG · diacylglycerol · DNA ligases · ERKs· GPCRs · GPCR families · guanylate cyclases · guanyl cyclase · inositol triphosphate · IP3 · MAP kinases · mitogen activated protein kinases · phosphatases · phosphodiesterases · phospolipases · phosphorylation · PKA · PKC · phospholipase C-gamma · protein kinase A · protein kinase C · protein tyrosine kinases (PTKs) · receptor tyrosine kinases · second messengers · second messenger cAMP · second messenger cGMP · signal transduction · two-component systems ·

Cell signaling


Response to



Membrane-penetrating receptors possessing intrinsic enzymatic activity.

EGF, FGF, insulin, PDGF receptors

Receptor tyrosine kinases (RTKs) capable of autophosphorylation as well as phosphorylation of other substrates.

Tyrosine phosphatases.

Guanylate cyclases (natriuretic peptide receptors).

Serine/threonine kinases, TGF-beta receptors

Receptor tyrosine kinases (RTKs),

Tyrosine phosphatases, (CD45).

Guanylate cyclases.

Serine/threonine kinases.

Membrane-penetrating receptors connected to intrinsic enzymatic activity. Activins, inhibins, bone morphogenetic proteins (BMPs), TGF-beta receptors Receptors (RTKs) coupled to intracellular protein tyrosine kinases by direct protein-protein interactions Protein tyrosine kinases
GPCRs hormones: adrenaline, glucagon, luteinizing hormone (LH), parathyroid hormone (PTH), adrenocorticotropic hormone (ACTH)*, rhodopsin**, growth factors***

GPCRs, or guanine nucleotide-binding protein-coupled receptors, or serpentine receptors.

***Receptors coupled to activation of phospholipase C-gamma

G-proteins → second-messenger → activated enzymes:

*adenylyl (adenylate) cyclasesecond-messenger cAMPcAMP-dependent protein kinase, (PKA)

**guanyl cyclasesecond messenger cGMPprotein kinase G (PKG)

***DAG & IP3 -protein kinase C (calcium dependent)

Intracellular receptors that migrate to the nucleus after binding to the ligand – to directly affect gene transcription Lipophilic steroid and thyroid hormones, incl. glucocorticoid, vitamin D, retinoic acid, and thyroid hormones. Hormone receptors are cytoplasmic proteins that bypass membrane-bound signal transduction pathways. Hormone-receptor complex translocates to the nucleus and binds to specific DNA sequences (hormone response elements, HREs).
two-component systems

Nutrient acquisition : nitrogen, phosphorus, carbon.


Energy metabolism : electron transport systems, uptake and catabolic machinery.

Developmental pathways.

Virulence : plasmid transfer (conjugation), degredative secretions, toxin production

Transmitter domain - histidine kinase protein autophosphorylates a histidine, then transfers the phosphoryl group to an aspartate residue of the partner response regulator protein Receiver domain - response regulator protein is activated by phosphorylation and then transmits the signal to its target
 Cell signaling  Receptor Tyrosine Kinases(RTK)  Second Messengers  Phosphate-handling Enzymes  · adenylyl (adenylate) cyclase · calcium ion · calcium ions · cAMP-dependent protein kinase · CDKs · cyclin-dependent kinases · DAG · diacylglycerol · DNA ligases · ERKs· GPCRs · GPCR families · guanylate cyclases · guanyl cyclase · inositol triphosphate · IP3 · MAP kinases · mitogen activated protein kinases · phosphatases · phosphodiesterases · phospolipases · phosphorylation · PKA · PKC · phospholipase C-gamma · protein kinase A · protein kinase C · protein tyrosine kinases (PTKs) · receptor tyrosine kinases · second messengers · second messenger cAMP · second messenger cGMP · signal transduction · two-component systems ·
Receptor Tyrosine Kinases (RTKs)
Class Examples Structural Features of Class
I EGF receptor, NEU/HER2,HER3 cysteine-rich sequences
II insulin receptor, IGF-1 receptor cysteine-rich sequences; characterized by disulfide-linked heterotetramers
III PDGF receptors, c-Kit Contain 5 immunoglobulin-like domains; contain the kinase insert
IV FGF receptors Contain 3 immunoglobulin-like domains as well as the kinase insert; acidic domain
V vascular endothelial cell growth factor (VEGF) receptor Contain 7 immunoglobulin-like domains as well as the kinase insert domain
VI hepatocyte growth factor (HGF) and scatter factor (SC) receptors Heterodimeric like the class II receptors except that one of the two protein subunits is completely extracellular. The HGF receptor is a proto-oncogene that was originally identified as the Met oncogene
VII neurotrophin receptor family (trkA, trkB, trkC) and NGF receptor Contain no or few cysteine-rich domains; NGFR has leucine rich domain
. . . since 10/06/06