Cell-Cell
Communication
Paracrine Factors & Cell
Surface Receptors
Paracrine
vs. Juxtacrine Interactions
• Juxtacrine Interactions - cell membrane
proteins on one cell surface interact with receptor proteins on adjacent cell
surfaces
• When proteins synthesized by one cell can diffuse over
small distances to induce changes in neighboring cells - paracrine
interactions
– Diffusible proteins are called paracrine factors or growth and differentiation factors
Mechanisms
of Inductive Interaction
Fibroblast
Growth Factors
•
Fibroblast growth
factor (FGF) - family of over 12 structurally related members
•
These activate a set of
receptor tyrosine kinases called fibroblast growth factor receptors (FGFRs)
•
When FGF binds - dormant
tyrosine kinase is activated - it phosphorylates certain proteins within the
responding cell
•
The proteins are now
activated & can perform new functions
–
E.g. Angiogenesis,
mesoderm formation & axon extension
FGF
Expression
The
Hedgehog Family
• Paracrine factors - used by embryo to induce
particular cell types and to create boundaries between tissues
• Vertebrates have at least 3 homologues of
Drosophila hedgehog gene
– sonic hedge (shh)
– desert hedge (dhh)
– indian hedgehog (ihh)
The
Hedgehog Family
• dhh - expressed in Sertoli cells of the testes
• ihh - expressed in the gut and in cartilage - also
important in postnatal bone growth
The
Hedgehog Family
•
Shh - most widely
used - made by notochord -
–
responsible for
patterning the neural tube - such that motor neurons are formed from the
ventral neurons & sensory
neurons are formed from the dorsal neurons
–
Also patterns the
somites such that the part closest to the notochord becomes the cartilage of
the spine
–
Mediates left-right
axis in chicks, anterior-posterior axis in limbs, induce regional specific
differentiation of the digestive tube & induce feather formation
The
Wnt Family
• Cystine rich glycoproteins - 15 members
• Wnt 1 - active in inducing the dorsal cells of the
somites to become muscle
• Also establishes polarity of limbs
• Also involve in urogenital system development
The
TGF-b
Superfamily
•
30 structurally
related members
–
TGF - transforming
growth factor
•
Involved in many
interactions from mammalian sex determination, regulating cell division,
epithelial cell branching into ducts of kidneys, lungs and salivary glands
•
BMP members - bone
formation, cell division, apoptosis (programmed cell death), cell migration
& differentiation, etc.
Cell
Surface Receptors
• Receptors that span the entire membrane that bind
paracrine factors (the ligand)
• This binding brings about a cascade of interacting
proteins that transmit a signal through a pathway from bound receptor to the
nucleus
– Called signal transduction pathways
Overview
of Signal Transduction Pathways
•
Ligand binds
extracellular region of receptor - induces a conformational change ( shape
change) of the receptor - transmitted to the cytoplasmic domain
•
This change gives the
cytoplasmic domain enzymatic activity
–
Usually a kinase
activity - use ATP to phosphorylate proteins
•
Now the
phosphorylated proteins become active
•
Eventually a cascade
of phosphorylation activates a dormant transcription factor
•
This then activates
or represses a particular set of genes
The
RTK-Ras Pathway
•
Receptor tyrosine
kinase is dimerized by the ligand
–
Ligands - fibroblast
growth factor, epidermal growth factors, plateletl-derived growth factors &
stem cell factor
–
Each can only bind one
or a small set of ligands
•
Receptors undergo a
conformational change - activating it
–
Can also now dimerize
with another RTK
–
They now phosphorylate
each other
•
Now recognized by
adapter protein
–
Acts a bridge that
links the phosphorylated RTK to an intracellular signaling system
The
RTK-Ras Pathway
•
Adapter protein
activates GNRP (guanine nucleotide releasing factor)
•
GNRP phosphorylates
Ras G protein
•
GAP (GTPase
activating protein) protein can now hydrolyze the phosphate bond - returns Ras to inactive state
•
Active Ras activates protein
kinase C (PKC) - this phosphorylates a series of kinases
•
Eventually, activated
ERK kinase alters gene expression by phosphorylating certain
transcription factors (determines which will be transcribed)
–
Also translation
factors can be activated to alter the level of protein synthesis
The
RTK-Ras Pathway
The
JAK-STAT Pathway
•
Casein gene activation
by prolactin from the ant. pituitary
•
This gene is activated
during the last phase of mammary gland development
•
Prolactin causes
dimerization of prolactin receptors
in the mammary duct epithelial cells
•
JAK 2 protein is
“hitched” to the receptors - these phorphorylate each other &
the dimerized protein - this
activates their kinase activity
•
This kinase activity
now adds a phosphate to a tyrosine residue (Y) of STAT 5 protein (for casein)
•
STAT can now dimerize
- now translocated into the nucleus - binds specific DNA region
•
Now in combination
with other transcription factors (already their) - activates transcription of
the casein gene
The
JAK-STAT Pathway
Wnt
Pathway
•
Wnt protein binds
with a receptor which is a member of the Frizzled family of proteins
•
The Frizzled protein
then activates Disheveled, allowing it to became an inhibitor of Glycogen
synthase kinase 3 (GSK-3)
•
GSK-3 if it were
active - prevents dissociation of b-catenin from the APC protein
•
Therefore by
inhibiting GSK-3, the Wnt signal frees b-catenin to associate with LEF protein to become an
active transcription factor
Wnt
Pathway
Hedgehog
Pathway
•
Hedgehog family of
proteins bind a receptor called Patched
–
Not a signal
transducer - bound to a signal transducer called smoothened protein
•
No Hedgehog protein
–
Patched protein
inhibits smoothened protein
–
In the absence of
hedgehog binding to Patched - Ci protein is tethered to microtubules
–
PKA and slimb proteins
can now cleave Ci into a transcriptional repressor that blocks transcription of
certain genes
Hedgehog
Pathway - No Hedgehog Protein
Hedgehog
Pathway - Presence of Hedgehog Protein
•
Hedgehog binds to
Patched - conformation changes - releasing inhibition of Smoothened protein
•
Smoothened protein
now releases Ci from mirotubules (may add phosphates to Cos2 & Fused
proteins
•
Also inactivates the
cleavage proteins PKA & Slimb
•
The Ci protein now
enters the nucleus - binds a CBP protein & act as a transcription activator
for certain genes
Hedgehog
Pathway - Presence of Hedgehog Protein