Cell-Cell Signaling

1. Cell-Cell Signaling Inductive Interactions

2. 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

3. 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

4. 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

5. Examples of Embryonic Inductions • Primary inductions • Mesoderm induction • Neural induction • Secondary inductions • Lens • Retina • Epidermal (hair, scales, feathers) • Tooth • Many organs

6. Sequential Inductive Interactions in Eye Formation

7. Sequential Inductive Interactions in Eye Formation Lens induction in amphibians

8. Sequential Inductive Interactions in Eye Formation Lens & retina formation in rodents 9.5 10.5 9 11.5 13

9. 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

10. 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.

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

12. 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

13. Mechanisms of Inductive Signaling Paracrine Signaling Juxtacrine Signaling

14. 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 Secreted Signaling Molecules

15. 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 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 Receptors for Soluble Signaling Molecules

16. ECM (ligand) Fibronectin Laminin Type IV collagen Integrins (receptor) CAMs (receptor) Cell Associated Signaling Molecules • Notch Family (receptor) • Delta Family (ligand) • Eph Family (receptor) • Ephrin Family (ligand)

17. Generalized Signal Transduction

18. RTK- Ras Pathway GEF GAP Grb2,Shc GEF like Sos

19. Evolutionary Conservation of Ras Pathway

20. Examples of RTK Signaling: Photoreceptor Differentiation

21. Examples of RTK Signaling: Photoreceptor Differentiation sev = sevenless boss = bride of sevenless ro = rough

22. Examples of RTK Signaling: Vulval Differentiation in C. elegans

23. Critical Mutations In RTK Pathways • Constitutively active receptors • Dominant negative receptors • Constitutively active Ras • Faulty GEFs or GAPs

24. Smad Pathway

25. Smad Pathway • Mesoderm specification • TGF - activin, Vg1, nodal • Ectoderm specification • BMP4, 7 • Dorsal specification (Drosophila) • Dpp

26. 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

27. Smad Pathway A More Detailed Look

28. Wnt - -catenin Pathway A more detailed look at Wnt signaling

29. Wnt - -catenin Pathway • Wnt = Drosophila wingless (wg) + mammalian int-1 • -catenin = armadillo • Dorsal specification in Xenopus • Segment polarity in Drosophila

30. 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

31. RTK-JAK-Stat pathway

32. JAK-Stat Pathway • Cytokine receptors • Interleukin, Interferon receptors • Blood cell differentiation • Chondrocyte differentiation • Mammary epithelium

33. Juxtacrine Signaling: Notch Pathway

34. Lateral Inhibition Specification of neural precursor cells in Drosophila neurectoderm Blue cell becomes neural precursor – GMC; white ones remain epidermis.

35. Focal Adhesion Complex

36. Signaling Through FAs

37. Signaling Through Cadherin-Associated RTKs

38. Eph receptor Eph RTK/Cell Adhesion Interactions & Signaling

39. Apoptotic Pathways