Signaling to Cells

Four general categories of signaling:

Cytoplasmic connections between cells
Cell-to-cell contact dependent signals
Cell-matrix mediated signals
Free diffusion of chemical signal between cells
Distant cells (hormones)
Adjacent cells (within interstitial space
Paracrine/Synaptic)

Insoluble signalling molecules

Juxtacrine signal
Cell-cell contacts at the plasma membrane

Integrins
L2

ICAM/VCAM/
Proteoglycans

Notch

Delta

Anchoring Junctions
Adherence
Junctions
Cadherin

Cadherin

Desmosomes

Tight Junctions
Signalling between the cells occurs at all these centres
Unlike other types of ligand mediated signalling (paracrine
and endocrine), juxtacrine signaling requires physical
contact between the two cells involved.

Occludin
Claudins
JAMs
Gap Junctions

Cell-Cell Contact
Highly specific
At Specialised Organelles
(Three/Four types)
(SIGNALLING AND TISSUE
ORGANISATION)

At Non Specialised cell regions

- (SIGNALLING AND
MOVEMENT/MIGRATION)

CAMS
CELL ADHESION
MOLECULES

Connexins
Occludin and claudin proteins
Cadherins
Integrins
Notch
Selectins
Ig superfamily CAMs
Ephrin signalling

btypes of specialised junctions

Occluding Junctions
1, TIGHT JUNCTIONS (vertebrates)
septate junctions (invertebrates)

ll-Cell Contacts
At Organized junctions/ Organelles
Anchoring Junctions
2, ADHERENCE JUNCTIONS
Actin attachment sites
3, DESMOSOMES
Intermediate filament attachment sites
Communicating Junctions
4, GAP JUNCTIONS
plasmodesmata (plants)
(5, ELECTRICAL SYNAPSES)

Communicating Junctions

oduce functional syncitia with cytoplasmatic connections between cells

Ca

2+

ATP
oAMP

Cell Gap Junctions-electrochemical signaling,

Gap Junctions

Gap Junctions are regulated

Eg The channels close at increased Ca2+ concentrations allowing
regulation of the degree of coupling to surrounding cells
Lucifer Yellow-Injected into retinal neuron
diffuses through open gap junctions

- Dopamine

+Dopamine

Other Ways of How Cell Signalling Occurs At

Organized Junctions
n introduction to phosphorylation
Nobel Prize in Physiology or Medicine for 1992
Edmond H. Fischer and Edwin G. Krebs
"reversible protein phosphorylation as a biological regulatory
mechanism".

MOLECULAR SWITCHES

Phosphorylation
serine
theonine
tyrosine

histidine and
aspartate
phosphorylation
occurs
in plants and
prokaryotes

Phosphorylation is reversible and regulatable.

Enzymes that add a phosphate to a hydroxyl side chain are called
kinases.

Reversible phosphorylation causes a conformational change in many

enzymes and receptors, leading to their activation or deactivation.
The addition of a phosphate to a weakly polar R group of an amino acid
residue turns a hydrophobic portion of a protein into an extremely hydrophilic
/ charged region.
This introduces a conformational change allowing protein binding to occur at
these regions.
In cell signalling;
Either a cell surface receptor is a kinase
which is activated by binding to its ligand
(see later lectures)

Or

A signal at the cell surface causes

transmembrane proteins to cluste
bring binding partners including ki

Receptor kinase activated by binding

its ligand
dimerization and autophosphorylation

Non-kinase receptors lack catalytic

domains and signal by clustering
and bringing binding partners
including kinases and their
substrates together

Intracellula
binding
partners

sphorylation of the receptor causes binding

s for other substrates to become accessible,
se are often kinases themselves which
ome phosphorylated and activated by the
eptor kinase

oducing a signalling cascade

1. Tight Junctions (occluding junctions)- seal

forming
Tight junctions result in a separatio
of a lumen about an epithelium

Apical

Basolateral

This means that tight junctions als

compartmentalise the membrane a
well as the surrounding of the cells
Ie the cells structurally polarise
have 2 separate surfaces

eighbouring cells with impermeable bonds

maintain an osmotic variance between regions
tant in gut, kidney and skin

1. Tight Junctions (occluding junctions)

Extracellul
ar

PKA
ZONAB

ealing strands forming transmembrane ridges

Two plasma membrane proteins- occludin and claudin form bands at

the apex of epithelial cells, these proteins interact with similar
proteins on neighbours forming an impermeable seal, also act as
signalling centre

2/3. Anchoring junctions link :A, actin cytoskeleton

filaments eg keratins
(adherence junctions),

B, Intermediate
(desmosomes)

Both contain members of the cadherin fam

3. Anchoring junctions

s-Ca2+ dependent adherence molecules, form cell-cell anchoring

Cadherins in different junctions

Classical cadherins junctions
Atypical cadherins -

Ca2+ causes dimerization of

Cadherins
The binding is homophilic

E, N, P and VE cadherins are present in adherens

Desmoglein, desmocollin in desmosomes

. Anchoring junctions link

Classical cadherins

Nonclassical cadherins

PI3
kinase

catenin

lso act as signalling centres concentrating kinases and their substrates eg PI3kin

nt for the Wnt pathway acting as a reservoir of the signalling molecule -catenin
es for instance cell division (cell cycle)

. Anchoring junctions link

Cadherins have roles in cell sorting

Cell Sorting is important in early steps in formation

the brain

E cadherin

EN..E

N cadherin

X
X
X
X
X X

Experimental over-expression of E cadherin

or under-expression of N cadherin at XXX stop
correct formation of the neural tube
Forms the much of the CNS

Spina Bifida

Encephaloceles
Hydranencephal
Iniencephaly

Anencephaly

CAMS
CELL ADHESION
MOLECULES

Connexins
Homophilic interactions
Occludin and claudin proteins
at cell surface organelles
(same type of molecule)
Cadherin
Notch
Selectins
Heterphilic interactions
Integrins
at on plasma membrane
Ig superfamily CAMs
Ephrin signalling

NotchNotch genefirst described in the fly

Notch Notch Receptor

Ligand
(Delta)

1917 Thomas Hunt Morgan

Cell I. Notch Ligand

expressor
Ligand 1 protease in Golgi

2 extracellular plasma membrane bound enzy

eg TACE
3 intracellular membrane bound enzyme
eg -secretase

Receptor

Cell 2. Notch Receptor

expressor

Rbpsuh normally a
-transcriptional repressor,
on binding to the notch tail
becomes an activator
Figure 15-76 Molecular Biology of the Cell
( Garland Science 2008)

Fly epithelial cells differentiate to nerve unless

inhibited by notch ligand (lateral inhibition)
(Notch
ligand-Delta

Figure 15-75 Molecular Biology of the Cell ( Garland Science 2008)

NOTCH EXPRESSION
Differentiated No expression
cells
Notch ligand and
Differentiatingreceptor

Notch signalling inhibits cell

division and induces proteins
expressed by differentiating
Dividing cells cells

cells

Notch ligand
Can induce a signal but dont
respond to one

Loss of notch ligand in skin (-/-)

Cell remain in dividing sate
results in hyperproliferation
of cells and tumour formation
(nb mouse ear skin is
normally thin)

Selectins are lectins- sugar bindingcells

proteins
Endothelial cell
c c
Endothelial cells

E/P Selectin produced by endothelial cells in infections/ infla

Extracellular

Bind to
sugars
on
glycoproteins
of leucocytes
in
the blood
P-selectin glycoprotein ligand-1 on
Leukocytes

PSGL-1

2 integrin

P-selectin
Induced by
inflammation

ICAM/VCAM

Cell Cell signalling

Many forms
All require direct contact between the cells
Crucial in maintaining cell and tissue homeostasis
(eg deregulated in cancers, required for correct development)
Both part of the structural requirements of a tissue
And to maintain cellular activity
eg WBC,