Cell Cell Interactions

Slide 1 · Cell–cell interactions

Junctions, epithelial polarity, biosynthesis and secretion

Foundations of cellular pathology

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish occluding, anchoring and communicating junctions.

Relate junctional proteins to the cytoskeleton and epithelial polarity.

Explain clinically relevant failures of cell adhesion.

Trace protein maturation through ER and Golgi.

Contrast classical secretion, unconventional release and extracellular vesicles.

Slide 3 · What junctional complexes accomplish

Seal

Restrict movement through spaces between epithelial cells.

Anchor

Couple neighboring cells or the extracellular matrix to the cytoskeleton.

Communicate

Transfer chemical or electrical information between adjacent cells.

Slide 4 · Three major classes of cell–cell junction

Class

Main role

Examples

Occluding

Paracellular barrier; Polarity boundary

Tight junctions

Anchoring

Mechanical continuity and force transfer

Adherens junctions; Desmosomes

Communicating

Chemical / electrical cell-to-cell signals

Gap junctions

Slide 5 · A polarized epithelium organizes several junction types

Apical surface

Tight

Adherens

Desmosome

Gap

Basal contact with extracellular matrix

Slide 6 · Tight junctions create an epithelial barrier

Cell A

Cell B

Tight junction seal

Neighboring epithelial cells form an apical seal.

The seal limits paracellular passage of ions and other molecules.

Barrier permeability is selective, not absolute.

Slide 7 · Two routes across an epithelial sheet

Transcellular route

A substance crosses the plasma membranes and cytoplasm of a cell.

Paracellular route

A substance passes between cells; Tight junctions restrict this path.

Slide 8 · Tight junctions form a mesh of contacts

Cell A

Cell B

Tight junction seal

Multiple molecular contacts create a continuous belt.

Freeze-fracture views show a tight mesh-like network.

The network is situated near the apical margin.

Slide 9 · Transmembrane components of tight junctions

Claudin family proteins contribute to the intercellular seal.

Tight junction–associated MARVEL proteins (TAMPs) are also present.

Protein complexes span adjacent plasma membranes.

The extracellular contacts act together as a barrier.

Slide 10 · Tight-junction cytoplasmic scaffold

ZO-1, ZO-2, ZO-3

Zonula occludens adaptor/scaffolding proteins.

Cingulin

Intracellular component of the tight-junction complex.

Functional assembly

Transmembrane components connect with cytoplasmic scaffolds.

Slide 11 · Tight junctions delineate membrane domains

APICAL DOMAIN

Membrane facing the lumen

BASOLATERAL DOMAIN

Membrane facing neighboring cells and the underlying tissue

The junctional belt helps maintain polarity.

Slide 12 · Barrier function and polarity are linked

The apical and basolateral membrane regions remain distinct.

Tight junctions define the boundary between these domains.

The junction therefore has both transport and organizational functions.

Slide 13 · Tight junctions are dynamically regulated

Baseline

Stable epithelial barrier and polarity.

Modification

Contacts change as the tissue responds.

Outcome

Controlled restructuring during repair or migration.

Slide 14 · Physiologic contexts for barrier remodeling

Epithelial repair

A dynamic junction allows the epithelium to reorganize while healing.

Inflammatory cell passage

Regulated changes permit inflammatory cells to cross epithelial-lined mucosal surfaces.

Slide 15 · Anchoring junctions are mechanically specialized

Adherens junction

Cadherin adhesion couples to actin microfilaments.

Desmosome

Cadherin adhesion couples to intermediate filaments.

Hemidesmosome

Integrins couple intermediate filaments to extracellular matrix.

Slide 16 · Cadherins support cell–cell adhesion

Cell A

Cell B

Homotypic cadherin binding

Transmembrane glycoproteins bridge adjacent cells.

Homotypic cadherin interactions occur across the intercellular space.

Intracellular connections determine mechanical behavior.

Slide 17 · Adherens junctions couple to actin

Cell A

Cell B

Cadherin → actin

Located commonly beneath tight junctions.

Adhesion proteins connect with actin microfilaments.

Actin coupling links adhesion to shape and motility.

Slide 18 · From adhesion to epithelial organization

E-cadherin

Cell–cell adhesive contact.

Actin linkage

Mechanical integration with cytoskeleton.

Cell behavior

Influence on cell shape and movement.

Slide 19 · E-cadherin loss can produce discohesive invasion

Reduced epithelial cohesion permits cells to infiltrate without remaining in cohesive groups.

Gastric carcinoma and lobular carcinoma of the breast as important examples.

Slide 20 · Discohesion: Two classic cancer examples

Gastric carcinoma

Some gastric cancers display a discohesive invasive pattern associated with E-cadherin loss.

Breast lobular carcinoma

Loss of epithelial E-cadherin explains the characteristic discohesive growth pattern.

Slide 21 · Application: Loss of epithelial cohesion

An infiltrative carcinoma is composed of poorly cohesive cells. Which junctional protein best accounts for this pattern?

A. E-cadherin

B. Connexin

C. Claudin

D. Cingulin

Slide 22 · Application: E-cadherin

Most consistent answer

E-cadherin

Mechanistic explanation

E-cadherin is an epithelial adherens-junction protein. Reduced adhesion can generate a discohesive invasion pattern.

Slide 23 · Desmosomes connect intermediate filaments

Cell A

Cell B

Cadherin–IF anchorage

Desmosomal cadherins bridge adjoining cells.

Intracellular plaques connect to intermediate filaments.

This architecture resists and distributes mechanical stress.

Slide 24 · Desmosomes dissipate mechanical force

Force applied

Stress reaches one epithelial cell.

Desmosomal links

Anchorage joins neighboring cytoskeletons.

Distributed load

Forces spread across several cells.

Slide 25 · Adherens junctions versus desmosomes

Property

Adherens junction

Desmosome

Intercellular adhesion

Cadherins

Cadherins

Intracellular linkage

Actin microfilaments

Intermediate filaments

Prominent function

Shape and motility

Resistance to tissue stress

Relative location

Near/below tight junction

Generally more basal

Slide 26 · Hemidesmosomes anchor cells to matrix

Basal cell

Extracellular matrix

Integrin linkage

The opposing structure is extracellular matrix, not another cell.

Integrins act as transmembrane connectors.

Intermediate filaments couple the cell to its basal substrate.

Slide 27 · Desmosome versus hemidesmosome

Property

Desmosome

Hemidesmosome

Attachment

Cell to cell

Cell to extracellular matrix

Transmembrane link

Cadherins

Integrins

Cytoskeletal partner

Intermediate filaments

Intermediate filaments

Mechanical role

Distributes cell-to-cell forces

Anchors the cell to its substrate

Slide 28 · Cell adhesion also senses mechanical load

Multiprotein assemblies

Focal adhesion complexes incorporate many interacting proteins.

Mechanical stimulus

Cells may experience shear or other loading forces.

Signal response

Adhesion-associated proteins can initiate intracellular signals.

Slide 29 · Two contexts for mechanotransduction

Vascular endothelium

Blood flow exposes endothelial cells to shear stress.

Cardiac myocytes

Mechanical loading in a failing heart provides an example of stress-linked signaling.

Slide 30 · Gap junctions connect two cytoplasms

Cell A

Cell B

Paired connexons form intercellular pores

Slide 31 · Connexon architecture: Paired connexin hexamers

Connexon in cell A

Connexon in cell B

Dock

One hexamer per cell; The aligned pair forms a pore.

Slide 32 · What can pass through a gap junction?

Ions and small metabolites.

Nucleotides and sugars.

Amino acids and vitamins.

Signals that coordinate neighboring cell activity.

Slide 33 · Gap junction permeability is regulated

Intracellular acidification

Lowered cytoplasmic pH rapidly reduces permeability.

Intracellular calcium elevation

Increased intracellular Ca²⁺ also reduces gap-junction permeability.

Slide 34 · Cardiac myocytes behave as a functional syncytium

Gap channels

Direct passage of small signaling substances.

Cell coordination

Intercellular calcium and electrical signaling.

Myocardial response

Waves of contraction across coupled cells.

Slide 35 · Junctional defects: Identify the lost function

Affected structure

Primary disrupted process

Relevant context

Tight junction

Epithelial barrier / polarity

Mucosal and epithelial surfaces

Adherens junction

Epithelial cell cohesion

Discohesive carcinomas

Desmosome

Force distribution

Mechanically stressed tissues

Gap junction

Intercellular signaling

Coordinated cardiac contraction

Slide 36 · Biosynthesis and secretion

Endoplasmic reticulum • Golgi apparatus • Secretory routes

Slide 37 · Cellular constituents undergo continual renewal

The cell continuously balances synthesis and degradation.

Structural proteins, enzymes, transcription factors and membranes all participate in ongoing turnover.

Slide 38 · The ER has three central synthetic roles

Membrane proteins

Production of proteins destined for cellular membranes.

Membrane lipids

Synthesis of lipid components for cellular organelles and surface.

Secreted proteins

Initial protein synthesis and processing before export.

Slide 39 · The ER is a continuous membrane system

Rough ER

CONTINUOUS LUMEN

RER: Ribosome-studded surface

Slide 40 · Rough versus smooth endoplasmic reticulum

Property

Rough ER (RER)

Smooth ER (SER)

Ribosomes

Attached to cytosolic face

Absent

Major emphasis

Protein synthesis and maturation

Lipid/steroid metabolism and Ca²⁺ storage

Specialization

Prominent in secretory protein cells

Prominent in steroidogenic cells and hepatocytes

Slide 41 · An ER signal sequence determines protein routing

Start

Ribosomes initially translate in cytosol.

Signal

N-terminal sequence directs nascent product to ER.

Insertion

Protein enters the ER lumen or membrane.

Slide 42 · Proteins with and without an ER signal peptide

With signal peptide

Translation is directed to the ER; Products are inserted into the membrane or conveyed into its lumen.

Without signal peptide

Translation remains on free cytosolic ribosomes; The proteins remain within the cytoplasm.

Slide 43 · RER establishes a pathway to the cell surface

Nascent peptide

Signal-directed ribosome recruitment to ER.

ER compartment

Membrane insertion or luminal delivery.

Downstream traffic

Transport toward Golgi for maturation and sorting.

Slide 44 · Proteins mature within the ER

Folding

Polypeptides acquire a functional conformation.

Oligomerization

Multiple protein chains may form complexes.

Chemical changes

Disulfide bond formation and N-linked glycosylation.

Slide 45 · N-linked glycosylation begins in the ER

Oligosaccharides are added to asparagine residues.

This modification begins before arrival in the Golgi.

The sugar chains undergo further modification during Golgi transit.

Slide 46 · ER chaperones participate in quality control

New proteins

Fold and assemble within the ER.

Chaperones

Assist maturation and retention.

Disposition

Correctly folded: Progress; Defective: Retain/degrade.

Slide 47 · Two outcomes of ER protein surveillance

Correctly folded cargo

Proteins complete modifications and proceed through secretory traffic.

Persistently misfolded cargo

Protein is retained within the ER and subjected to degradation.

Slide 48 · CFTR Phe508 deletion: A proteostasis example

Deletion

Loss of phenylalanine at position 508.

ER handling

Abnormal folding triggers retention/degradation.

Functional result

Reduced CFTR expression at cell surface.

Slide 49 · Unfolded protein response is activated by ER overload

Misfolded proteins accumulating beyond ER quality-control capacity trigger the unfolded protein response (UPR).

The response aims to restore folding homeostasis.

Slide 50 · The unfolded protein response: Three outcomes

Reduce input

Overall cellular protein synthesis is reduced.

Increase capacity

Chaperone protein production rises.

If unresolved

Persistent stress can trigger apoptosis.

Slide 51 · Escalation from ER stress to apoptosis

Protein overload

Misfolded proteins accumulate.

UPR activation

Adaptation attempts to control the burden.

Failure

Uncorrected stress can lead to programmed cell death.

Slide 52 · ER-to-Golgi transport and cargo maturation

Rough ER

Synthesis, folding, initial N-linked sugars

Golgi cisternae

Sequential sugar processing

Trans Golgi

Cargo sorting and dispatch

Vesicle-mediated transfer; Ordered processing

Slide 53 · Golgi traffic progresses from cis to trans

ER →

Cis face

Trans face

Export

Ordered cisternal processing and sorting

Slide 54 · Cisternal progression supports ordered processing

Cis side

Receives newly transported ER cargo.

Maturation

Golgi cisternae progress toward the trans side.

Recycling

Vesicles return resident enzymes to earlier regions.

Slide 55 · N-linked and O-linked glycosylation

Feature

N-linked

O-linked

Amino acid

Asparagine

Serine or threonine

ER step

Initial oligosaccharide addition

—

Golgi step

Stepwise pruning and extension

Oligosaccharide addition

Slide 56 · Mannose-6-phosphate directs lysosomal enzymes

Cargo

Selected enzymes acquire mannose-6-phosphate labeling.

Recognition

M6P receptor recognizes modified cargo.

Destination

Transport into the lysosomal pathway.

Slide 57 · Glycosylation affects more than protein structure

Lysosome delivery

Selected sugar marks enable intracellular sorting.

Adhesive interactions

Glycosylation influences cell–cell and cell–matrix contacts.

Clearance

Sugar-related changes participate in removal of senescent blood cells.

Slide 58 · The trans Golgi network directs cellular cargo

Trans Golgi

Sorting hub

Plasma membrane

Secretory vesicles

Other organelles

Slide 59 · Secretory cell morphology reflects Golgi activity

Goblet cell

Prominent Golgi activity supports high-volume secretion of polysaccharide-rich mucus.

Plasma cell

The Golgi appears as a perinuclear hof on H&E sections in antibody-producing cells.

Slide 60 · Smooth ER performs distinct cellular tasks

Transport interface

A transition zone can generate ER-to-Golgi vesicles.

Metabolism

Prominent in steroidogenic and xenobiotic-processing cells.

Calcium homeostasis

Sequesters intracellular calcium for signaling.

Slide 61 · Smooth ER is enlarged in selected cell types

Gonadal and adrenal cells

Specialized for steroid-hormone biosynthesis.

Hepatocytes

Contain SER supporting metabolism of lipid-soluble molecules.

Slide 62 · Xenobiotic exposure can induce smooth ER

Repeated exposure

Compound processed by SER enzymes.

Enzymatic demand

Cytochrome P450 systems catabolize the compound.

Adaptive response

Smooth ER hyperplasia may develop.

Phenobarbital is a source example of an inducing exposure.

Slide 63 · Sarcoplasmic reticulum governs calcium cycling

Sarcoplasmic reticulum

Specialized smooth ER: Ca²⁺ reservoir

Muscle cytosol

Ca²⁺ rise triggers contraction

Release

Reuptake

Release → contraction | sequestration → relaxation

Slide 64 · Classical versus unconventional secretion

Feature

Classical pathway

Unconventional release

Core route

ER → Golgi → secretory or surface destination

Release without the classical ER–Golgi route

Illustrations

Secretory proteins and membrane cargo

IL-1β; α-synuclein; Extracellular vesicles

Teaching focus

Ordered maturation and sorting

Alternative mechanisms of export

Slide 65 · Examples of unconventional secretion

Interleukin-1β (IL-1β): A major proinflammatory cytokine.

α-Synuclein: A protein implicated in Parkinson disease.

Extracellular vesicles: Membrane-bound particles released into extracellular space.

Slide 66 · Extracellular vesicles export molecular cargo

Forms

Exosomes and microvesicles are examples.

Contents

May contain proteins, lipids and nucleic acids.

Destination

Released to extracellular fluid and can enter biofluids.

Slide 67 · Extracellular vesicles have biomarker potential

Vesicles in blood and other biofluids can be investigated as sources of tissue-derived biomarkers.

This is a rationale for liquid-biopsy research; The source does not give clinical sensitivity or specificity.

Slide 68 · Transport processes at a glance

Process

Principal components

Consequence

Junction assembly

Transmembrane proteins + scaffolds

Adhesion, polarity and intercellular signaling

Classical secretion

ER + Golgi + transport vesicles

Mature cargo reaches targeted location

Unconventional export

Alternative release routes / vesicles

Cell-derived molecules enter extracellular space

Slide 69 · Application: A protein fails to reach the surface

A mutant membrane protein is retained and degraded in the ER because it cannot fold properly. Which mechanism is most directly implicated?

A. ER protein quality control

B. Loss of connexon docking

C. Desmosomal cadherin binding

D. Paracellular ion transport

Slide 70 · Application: ER quality control

Most consistent answer

ER retention and degradation

Mechanistic explanation

The Phe508 deletion in CFTR is the source example: Abnormal folding reduces delivery to the plasma membrane.

Slide 71 · Principal teaching points

Tight junctions regulate paracellular movement and epithelial polarity.

Cadherin-based junctions connect cells to actin or intermediate filaments.

Integrin-based hemidesmosomes anchor cells to extracellular matrix.

Gap junctions coordinate adjacent cells through direct communication.

ER and Golgi produce, mature, surveil and route cellular cargo.

Slide 72 · Primary reading

Core textbook

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition (2026). Chapter 1: The Cell as a Unit of Health and Disease; Cell–Cell Interactions and Biosynthesis and Secretion, pp. 11–13.

Illustrations in this lecture are original editable schematics based on the supplied text.