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– 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 9.5 10.5

11.5 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 InteractionsEpithelial 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

• 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, TGFRI/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 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

• ECM (ligand)

– Fibronectin– Laminin– Type IV collagen

• Integrins (receptor)

• CAMs (receptor)

•Notch Family (receptor)

•Delta Family (ligand)

•Eph Family (receptor)

•Ephrin Family (ligand)

Generalized Signal Transduction

RTK- Ras Pathway

GAP

Grb2,Shc

GEF like Sos

GEF

Evolutionary Conservation of Ras Pathway

Examples of RTK Signaling: Photoreceptor Differentiation

Examples of RTK Signaling: Photoreceptor Differentiation

sev = sevenlessboss = bride of sevenlessro = rough

Examples of RTK Signaling: Vulval Differentiation in C. elegans

Critical Mutations In RTK Pathways

• 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 = Drosophila wingless (wg) + mammalian int-1

-catenin = armadillo

• Dorsal specification in Xenopus• Segment polarity in Drosophila

Wnt - -catenin Pathway

• Inhibitors of wnt signaling– Frisbee– Dickkopf– Cerberus

• Look like extracellular portion of frizzled• Bind to wnts and prevent their interaction

with frizzled

Wnt - -catenin Pathway Inhibitors

RTK-JAK-Stat pathway

JAK-Stat Pathway

• Cytokine receptors– Interleukin, Interferon receptors– Blood cell differentiation

• Chondrocyte differentiation• Mammary epithelium

Juxtacrine Signaling: Notch Pathway

Lateral InhibitionSpecification 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 Cadherin-Associated RTKs

Eph RTK/Cell Adhesion Interactions & Signaling

Eph receptor

Apoptotic Pathways