Cell-Cell Signaling
Inductive Interactions
Induction: proximate interactions
• Close range interactions
• Inducer
– Tissue doing the inducing
– Emits a signal
• Secreted peptides
• Cell associated proteins
• Responder
– Tissues/cells that receive the signal
– Change as a result of receiving signal
– Express receptor to interact with secreted signaling
molecule
Induction
• Competence
– The ability of a group of cells to respond to the
inducing signal
– Essentially means competent cells have
receptors and all necessary second messengers
necessary to respond appropriately to the signal
Types of Inductive Interactions
• Instructive interactions
– Signals cause a response
– Signals are required for the response
– A specific response is induced
– Ligand-receptor interactions setting off signal cascade
• Permissive interactions
– Signals allow a response
– Signals do not designate a specific response
– ECM allows differentiation
Examples of Embryonic
Inductions
• Primary inductions
– Mesoderm induction
– Neural induction
• Secondary inductions
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–
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–
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Lens
Retina
Epidermal (hair, scales, feathers)
Tooth
Many organs
Sequential Inductive Interactions
in Eye Formation
Sequential Inductive Interactions
in Eye Formation
Lens induction in amphibians
Sequential Inductive Interactions
in Eye Formation
Lens & retina
formation in
rodents
9.5
9
11.5
10.5
13
Epithelial-Mesenchymal
Interactions
• Epithelial cells
– Cells of epidermal or endodermal origin
– have distinct epithelial morphology
• Mesenchymal cells
– Cells of mesodermal origin
– Have a distinct mesenchymal morphology
Mesenchymal-Epithelial
Interactions
Epidermis is competent
to differentiate into
epidermal structures
(follicles). The dermis
is the source of
inducing signals to
specify the type of
epidermal structure
formed.
Mesenchymal-Epithelial Interactions
Epithelial tissue can only
respond within the limits of
its genetic programming.
The age old question Does a chicken have
lips?
Mechanisms of Inductive
Signaling
• Paracrine signaling
– Secreted, diffusible signaling molecules
• Peptide growth factors (PGFs) or peptide inducing factors (PIFs)
• Not exactly the same as hormones – not secreted into bloodstream but
into intercellular space
• Signaling at a limited distance
• Juxtacrine signaling
– Non-soluble signaling molecules
• Integral or membrane associated proteins
• Signaling occurs at point of cell-cell contact
Mechanisms of Inductive
Signaling
Paracrine Signaling
Juxtacrine Signaling
Secreted Signaling Molecules
•
•
•
•
FGF Family
Hedgehog Family
Wnt Family
TGF Superfamily
– TGF Family
– Activin Family
– BMP Family
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•
•
•
•
•
•
EGF Family
PDGF Family
Retinoids
HGF/Scatter Factor
Neurotrophins
Semaphorins
Cytokines
Receptors for Soluble Signaling Molecules
• Receptor Tyrosine Kinase
(RTK) pathway
– FGFR, EGFR, PDGFR
– Receptor coupled to ras signal
transduction cascade
• Smad pathway
– Bipartite Serine/Threonine
Kinase Receptors
– AcRI/II, TGFRI/II, BMPRI/IIs
– Receptors activate Smad
transcription factors
• Wnt--catenin pathway
– Frizzled family of receptors
– Activation of pathway allows catenin to enter nucleus
• JAK-STAT pathway
– Peptide hormone or cytokine
receptor coupled to a Jak
cytoplasmic tyrosine kinase
– Jaks activate STAT
transcription factors
• Hedgehog Pathway
– Patched and smoothened coreceptors
– Activation of pathway
converts Ci txn’l repressor to
activator
• Steroids/Retinoids
– Nuclear/DNA binding
receptors
– Hormone permits entry into
nucleus, alters DNA binding
conformation, or allows
interaction with co-txn factors
Cell Associated Signaling
Molecules
•Notch Family (receptor)
•Delta Family (ligand)
•Eph Family (receptor)
•Ephrin Family (ligand)
• ECM (ligand)
– Fibronectin
– Laminin
– Type IV collagen
• Integrins (receptor)
• CAMs (receptor)
Generalized Signal Transduction
RTK- Ras Pathway
GEF
GAP
Grb2,Shc
GEF like Sos
Evolutionary Conservation of Ras
Pathway
Examples of RTK Signaling:
Photoreceptor Differentiation
Examples of RTK Signaling:
Photoreceptor Differentiation
sev = sevenless
boss = bride of sevenless
ro = rough
Examples of RTK Signaling: Vulval
Differentiation in C. elegans
Critical Mutations In RTK
Pathways
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•
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Constitutively active receptors
Dominant negative receptors
Constitutively active Ras
Faulty GEFs or GAPs
Smad Pathway
Smad Pathway
• Mesoderm specification
– TGF - activin, Vg1, nodal
• Ectoderm specification
– BMP4, 7
• Dorsal specification (Drosophila)
– Dpp
Smad Pathway Inhibitors
• Inhibitory Smads
– Bind to smads 1, 5 or 2, 3 in the hypophosphorylated
state & prevent interaction with smad4
– Phosphorylation of smads 1,5, 2 & 3 disrupt inhibitory
smad interaction and allow smad 4 binding
• Noggin
• Chordin
– Bind to BMPs and prevent their interaction with
receptors
Smad Pathway
A More Detailed Look
Wnt - -catenin
Pathway
A more detailed
look at Wnt
signaling
Wnt - -catenin Pathway
• Wnt = Drosophila wingless (wg) +
mammalian int-1
• -catenin = armadillo
• Dorsal specification in Xenopus
• Segment polarity in Drosophila
Wnt - -catenin Pathway
Inhibitors
• Inhibitors of wnt signaling
– Frisbee
– Dickkopf
– Cerberus
• Look like extracellular portion of frizzled
• Bind to wnts and prevent their interaction
with frizzled
RTK-JAK-Stat pathway
JAK-Stat Pathway
• Cytokine receptors
– Interleukin, Interferon receptors
– Blood cell differentiation
• Chondrocyte differentiation
• Mammary epithelium
Juxtacrine Signaling: Notch Pathway
Lateral Inhibition
Specification of neural
precursor cells in
Drosophila neurectoderm
Blue cell becomes neural
precursor – GMC; white
ones remain epidermis.
Focal Adhesion Complex
Signaling Through FAs
Signaling Through CadherinAssociated RTKs
Eph RTK/Cell Adhesion
Interactions & Signaling
Eph receptor
Apoptotic Pathways