CellCell Signaling

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Cell-Cell Signaling

• Inductive Interactions

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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

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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

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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

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Examples of Embryonic Inductions

• Primary inductions
• Mesoderm induction
• Neural induction
• Secondary inductions
• Lens
• Retina
• Epidermal (hair, scales, feathers)
• Tooth
• Many organs

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Sequential Inductive Interactions in Eye Formation
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Sequential Inductive Interactions in Eye Formation
Lens induction in amphibians
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Sequential Inductive Interactions in Eye Formation
Lens retina formation in rodents
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10.5
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11.5
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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

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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.
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Mesenchymal-Epithelial Interactions
Epithelial tissue can only respond within the
limits of its genetic programming.
The age old question - Does a chicken have lips?
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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

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Mechanisms of Inductive Signaling
Paracrine Signaling
Juxtacrine Signaling
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Secreted Signaling Molecules

• FGF Family
• Hedgehog Family
• Wnt Family
• TGF? Superfamily
• TGF? Family
• Activin Family
• BMP Family

• EGF Family
• PDGF Family
• Retinoids
• HGF/Scatter Factor
• Neurotrophins
• Semaphorins
• Cytokines

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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 co-receptors
• Activation of pathway converts Ci txnl 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

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Cell Associated Signaling Molecules

• ECM (ligand)
• Fibronectin
• Laminin
• Type IV collagen
• Integrins (receptor)
• CAMs (receptor)

• Notch Family (receptor)
• Delta Family (ligand)

• Eph Family (receptor)
• Ephrin Family (ligand)

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Generalized Signal Transduction
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RTK- Ras Pathway
GAP
GEF
Grb2,Shc
GEF like Sos
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Evolutionary Conservation of Ras Pathway
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Examples of RTK Signaling Photoreceptor
Differentiation
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Examples of RTK Signaling Photoreceptor
Differentiation
sev sevenless boss bride of sevenless ro
rough
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Examples of RTK Signaling Vulval Differentiation
in C. elegans
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Critical Mutations In RTK Pathways

• Constitutively active receptors
• Dominant negative receptors
• Constitutively active Ras
• Faulty GEFs or GAPs

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Smad Pathway
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Smad Pathway

• Mesoderm specification
• TGF? - activin, Vg1, nodal
• Ectoderm specification
• BMP4, 7
• Dorsal specification (Drosophila)
• Dpp

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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

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Smad Pathway
A More Detailed Look
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Wnt - ?-catenin Pathway
A more detailed look at Wnt signaling
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Wnt - ?-catenin Pathway

• Wnt Drosophila wingless (wg) mammalian
  int-1
• ?-catenin armadillo
• Dorsal specification in Xenopus
• Segment polarity in Drosophila

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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

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RTK-JAK-Stat pathway
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JAK-Stat Pathway

• Cytokine receptors
• Interleukin, Interferon receptors
• Blood cell differentiation
• Chondrocyte differentiation
• Mammary epithelium

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Juxtacrine Signaling Notch Pathway
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Lateral Inhibition
Specification of neural precursor cells in
Drosophila neurectoderm
Blue cell becomes neural precursor GMC white
ones remain epidermis.
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Focal Adhesion Complex
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Signaling Through FAs
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Signaling Through Cadherin-Associated RTKs
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Eph RTK/Cell Adhesion Interactions Signaling
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Apoptotic Pathways