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.

 Cell signaling  Second Messengers  RTKs 

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

Immune Cytokines
Cytokine class	Producer cell/tissue	Target cell	Functions
Granulocyte/Monocyte Colony Stimulating Factor (CSF)
G-CSF	endothelium, macrophages	neutrophil progenitor cells	growth and differentiation of neutrophils
GM-CSF	Th cells	progenitor cells	growth and differentiation of monocytes and dendritic cells
M-CSF	thymic epithelial cells (TEC), PMN, chondrocytes, glomerular mesangial cells, Ishikawa cells	macrophage lineage	lymphohematopoietic growth and differentiation of monocytes, enhances expression of differentiation- antigens and stimulates chemotactic, phagocytic, and cytotoxic activities of monocytes
Interleukins
IL-1a IL-1b pro-inflammatory	monocytes macrophages B cells dendritic cells	Th cells	costimulation
		B cells	maturation and proliferation
		NK cells	activation
		various	inflammation, acute phase response, fever
IL-2 hematopoietin	Th1 cells	activated T cells and B cells, NK cells	cell growth, proliferation, activation, synthesis of antibodies
IL-3 (multi-CSF) hematopoietin	Th cells NK cells	stem cells	growth and differentiation
		mast cells	growth, and histamine release
IL-4 hematopoietin	Th2 cells	activated B cells	proliferation and differentiation IgG1 and IgE synthesis
		macrophages	MHC Class II
		T cells	proliferation
IL-5 hematopoietin	Th2 cells	activated B cells	proliferation and differentiation IgA synthesis
IL-6 hematopoietin pro-inflammatory 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	monocytes macrophages Th2 cells stromal cells	activated B cells	differentiation into plasma cells → secretion of antibodies
		T cells	costimulator of T cells
		stem cells	differentiation
		various	acute phase response
		neurons, osteoblasts	neuronal differentiation, bone loss
IL-7	marrow stroma thymus stroma	stem cells	differentiation into progenitor B and T cells
IL-8 chemokine	macrophages endothelial cells	neutrophils	chemotaxis
IL-10	Th2 cells	macrophages	inhibition of macrophage function, cytokine production
		B cells	activation
IL-12	macrophages B cells	activated Tc cells	differentiation into CTL (with IL-2)
		NK cells	activation
Interferons  Interferons
IFN-a	leukocytes	various	viral replication MHC I expression
IFN-b	fibroblasts	various	viral replication MHC I expression
IFN-g	Th1 cells, Tc cells, NK cells	various	viral replication
		macrophages	MHC expression
		activated B cells	Ig class switch to IgG2a
		Th2 cells	proliferation
		macrophages	pathogen elimination
Macrophage Inflammatory Proteins
MIP-1a chemokine	macrophages	monocytes, T cells	chemotaxis
MIP-1b chemokine	lymphocytes	monocytes, T cells	chemotaxis
Transforming Growth Factor
TGF-b	T cells, monocytes	monocytes, macrophages	chemotaxis
		activated macrophages	IL-1 synthesis
		activated B cells	IgA synthesis
		various	proliferation
Tumor Necrosis Factor
TNF-a pro-inflammatory	macrophages, mast cells, NK cells	macrophages	CAM and cytokine expression
		tumor cells	cell death
TNF-b lymphotoxin-α (LT) pro-inflammatory	Th1 and Tc cells	phagocytes B cells	phagocytosis, with no production; activation effector cells to infection sites, leukocyte adhesion to endothelial cells, peripheral lymphoid organogenesis, stimulation of B cells
		tumor 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]	Ligands	Functions
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.
integrins
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		Actions
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
Gene	Receptor	Function
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.

Messenger	Stimulator	Enzyme	Acts on
cAMP	Adrenaline, glucagon, luteinizing hormone (LH), parathyroid hormone (PTH), adrenocorticotropic hormone (ACTH)	adenylyl (adenylate) cyclases	cAMP-dependent protein kinase, (PKA), gene transcription
cGMP	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

Type	Response to	Receptor	Enzyme
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) cyclase → second-messenger cAMP → cAMP-dependent protein kinase, (PKA) **guanyl cyclase → second messenger cGMP → protein 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. Chemotaxis. 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