Cell-cell adhesion occurs through morphological structures and CAMs

Cell adhesion is a dynamicProcess that plays an important role in embryo development

Cell-cell adhesion is tissue-specific

Molecular structure of Cadherins

1. Cadherin was identified via monoclonal antibody generationand in vitro aggregation assays

2. E-cadherin was named alsoas uvomorulin

Cadherin binds each other via homophilic binding

Mode of cadherin interaction

Mode of cadherin interaction

Expression of cadherin is dynamically controlled during embryogenesis

Catenins are adaptor proteins that bind cadherin to actin cytoskeleton

Binding sites for classical cadherin

-catenin occurs both at cell adhesion site and within nucleus

Phosphorylated -catenin is degraded through ubiquitination pathway

Nuclear -catenin enhances cell proliferation

Mutated APC complex promotes entry of-catenin into nucleus and enhances cell proliferation

Inappropriate expression of -catenin induces cell cycle progression in intestine

-catenin binds diverse proteins

Molecular structure of N-CAM

1.N-CAM comprises 5 Ig-likeextracellular domains

2. Mode of binding is via heterophilic interaction

Molecular structure of Selectin

Classification of cell junctions

Components of junctional complex

General structure of anchoring junctions

Intermediate junction (adhesion belt)

E-cadherin constitutes the core of intermediate junction

Desmosome

Desmosome

Molecular components of desmosomes

Desmosomes connect epithelial cells as a whole

Tight junctions prevent passage of extracellular material into intracellular space

Molecular components of hemidesmsomes

Cell adhesion needs cytoskeleton

Gap junctions are made up of connexons with a 2nm intracellular gap

Each connexon is made of 6 subunits (connexin) and controls passage of molecules with MW < 1000 Da

Cell-matrix interaction

Extracellular matrix reorganizes cytoskeleton of transformed cells

Integrin functions as linking molecule for ECM and cytoskeleton

Colocalization of integrin and actin cytoskeleton

Molecular structure of Integrin

Focal adhesion

Focal complex Focal contacts

Rac dependent formation of focal complex

Dentritic network model of actin assembly

Molecular constitutents of focal complex

How focal complex is assembled into focal contact ?

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Rho dependent growth of focal contacts

Myosin light chain (MLC) phosphorylation is modulated by Rho

Assembly of focal contact is mediated through integrin clustering and formation of stress fibers

Feedback loop controlling the formation and growth of focal contacts

FAKSrc

Basic rules that regulate the fate of a focal contact

1. initially binding of integrins to their ECM partners takes place at the leading edge

2. Rac is activated and drives the formation of focal complex by activating the assembly of dynamic actin network in the lamellipodium

3. Rho drives the maturation of focal contacts by the activation of both Dia and ROCK

4. Pulling of focal contacts promotes tension-dependent incorporation of new components into the nascent adhesion sites, leading to its growth

Anoikis: type of apoptosis for cells that denied adhesion

Integrins transmit signals through ligation-dependent recruitment of non-receptor tyrosine kinase from the focal adhesion kinase (FAK) and Src

Integrin-mediated resistance to stress-induced apoptosis via Ras-PI3-kinase-Akt pathway

Role of ERK activation in integrin resistance to stress-induced apoptosis

FAK regulates cellular locomotion

Deficiency of FAK results in arrest of cell movement