1. Copyright © 2005 Pearson Prentice Hall, Inc. http://aimediaserver.com/studiodaily/videoplayer/?src=harvard/harvard.swf&width=640&height=520

2. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling General Principles of Cell Signaling –signaling cell => signaling molecule binds to receptor molecule on target cell Signaling Distances: => Four Types of SignalingF.16-3 Endocrine Paracrine Neuronal Contact Dependent T16-1 testosterone, TGF-b, acetylcholine, Delta

3. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling Receptor: –Each Target Cell Responds to Limited Set of Signals (origin of complexity) –Must have receptor molecule for the signaling molecule (thousands of receptors) –Different receptors for same signal on different cells F16-5 A & C or F16-5 B & C

4. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling Intracellular Signaling Pathways: –Same receptor molecule can interact w/many intracellular relay systems so same signal & same receptor => different effects in different cells F16-5A & B –Same relay system many act on many different intracellular targets F16-7

5. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling Target Cell Action: Depends upon ---- F16-6 –Signals That are Present –Receptors That Target Cell Synthesizes –Intracellular Relay Systems = Signaling Cascades That Target Cell Synthesizes –Intracellular Targets That Target Cell Synthesizes F16-8 Any target cell type at any one time has only a subset of all possible –Receptors, –Intracellular Relay Systems, –Intracellular Targets

6. Copyright © 2005 Pearson Prentice Hall, Inc. 16_06_extracellular_sig.jpg

7. Copyright © 2005 Pearson Prentice Hall, Inc. 16_08_cascades.jpg

8. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling Signaling Cascades: Critical Functions pp. 539 & 540 (be able to apply each function to components of the signaling cascades we study) Transduce Signal Relay signal from point of reception to point of response production Amplify F16-29 Distribute signal to >1 process simultaneously Modulate signal to fit other internal & external conditions

9. Copyright © 2005 Pearson Prentice Hall, Inc. 16_29_amplifies_light.jpg

10. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling Extracellular Signaling Molecules: Two Types of Extracellular Signaling Molecules Based on Ability to Cross Plasma Membrane F.16-9 Cross Plasma Membrane (hydrophobic) –NOdirectly activate intracellular enzymes F16-10 vascular endothelial cells release NO activates guanyl cyclase in smooth muscle => relaxation => vasodilation guanyl cyclase: GTP = cGMP nitroglycerine, erection, Viagra (blocks cGMP reakdown) –Steroid Hormones F16-11 & 12

11. Copyright © 2005 Pearson Prentice Hall, Inc. 16_09_molecules_bind.jpg

12. Copyright © 2005 Pearson Prentice Hall, Inc. 16_10_Nitric_oxide.jpg

13. Copyright © 2005 Pearson Prentice Hall, Inc. 16_11_phobic_hormone.jpg

14. Copyright © 2005 Pearson Prentice Hall, Inc. 16_12_cortisol.jpg

15. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling Ligand for Cell Surface Receptor (hydrophilic: don’t cross plasma membrane) F16-1 –Ion-Channel-Linked Receptors F16-14A convert chemical to electrical signals –G-protein-linked Receptors F16-14B,& F16-17 ligand binding => G-Protein activation by exchange bound GDP for GTP Common structure = 7-pass membrane protein F16-16 –Enzyme-Linked Receptors F16-14C

16. Copyright © 2005 Pearson Prentice Hall, Inc. 16_14_3_basic_classes.jpg

17. Copyright © 2005 Pearson Prentice Hall, Inc. 16_13_receptor_protein.jpg

18. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling Intracellular Signaling Molecules – Many are Molecular Switches –switched on by signaling molecule, must also be turned off Most common switching mechanisms T16-2 nicotine, morphine & heroin –phosphorylation F16-15A –signal activated kinase; –dephosphorylation – phosphatase –GTP binding proteins: F16-15B –GDP bound = inactive, –GTP bound = active

19. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling G-Protein Linked Receptors Largest family of cell-surface receptors – 100s of members 7-pass Transmembrane Proteins F16-16 Ligand binding Activates G-Protein subunits F16-17 Inactivated by hydrolysis of its own bound GTP F16-18 cholera toxin prevents this; G protein stays on => water & ion loss

20. Copyright © 2005 Pearson Prentice Hall, Inc. 16_18_Gprot_subunit.jpg

21. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling G-Protein Linked Receptors Action mechanisms –Some regulate ion channels F16-19 Some activate membrane-bound enzymes => increase “2nd messengers” F16-20 –2nd messenger = cAMP F16-24 adenyl cyclase => ATP to cAMP cAMP phosphodiesterase => cAMP to ATP cAMP dependent protein kinase activation by Camp cAMP => both rapid and slow responses F16-23 –2nd messengers = IP3 & DAG phospholipase c => IP3 & DAG F16-25 IP3 => opens ER Ca+2 channels. >>>> cytoplasmic Ca+2. > free Ca+2 => many effects DAG (w free Ca+2) => activated PKC to inner face of membrane activated PKC => many effects –2nd messenger = Ca+2 free Ca+2 => many effect via Ca+2 binding proteins e.g. calmodulin & calmodulin dependent protein kinases

22. Copyright © 2005 Pearson Prentice Hall, Inc. Some regulate ion channels

23. Copyright © 2005 Pearson Prentice Hall, Inc. Some activate membrane-bound enzymes => increase “2nd messengers”

24. Copyright © 2005 Pearson Prentice Hall, Inc. 2nd messenger = cAMP

25. Copyright © 2005 Pearson Prentice Hall, Inc. 2nd messenger = cAMP

26. Copyright © 2005 Pearson Prentice Hall, Inc. 16_23_slowly_rapidly.jpg

27. Copyright © 2005 Pearson Prentice Hall, Inc. 2nd messengers = IP3 & DAG

28. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling Enzyme Linked Receptors Transmembrane proteins cytoplasmic domain is enzyme or interacts w enzyme When ligand is soluble signaling protein, action usually gene regulation – slow Receptor Tyrosine Kinases (= RTK) –Ligand binding => –dimerization of RTK subunits => –activate kinase activity => –binding of intracellular signaling proteins F16-30 –protein phosphatases remove P from RTK Intracellular signaling proteins include –a phospholipase that, like PLC, activates IP3 pathway –a PI 3-kinase that PO4s membrane IPLs, then bind other signaling proteins –Ras: important in loss of control of cell division, & thus in cancer

29. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling Enzyme Linked Receptors All RTKs Activate Ras –Ras = One of lg family of monomeric GTP Binding Proteins F16-31 NOT trimeric like G protein resembles a subunit of trimeric G proteins Activated by binding GTP Inactivated by hydrolysis of its own bound GTP Activated Ras activates MAP kinase phosphorylation cascade F16-32 Effect of inactivating Ras => cell ignores signals to divide Effects of permanent activation of Ras => cell acts as if constantly receiving mitogens Mutant Ras in cancer cells (~30% of all human cancers have mutant) => constantly “on”

30. Copyright © 2005 Pearson Prentice Hall, Inc. 16_31_active_Ras.jpg

31. Copyright © 2005 Pearson Prentice Hall, Inc. 16_32_MAP-kinase.jpg

32. Copyright © 2005 Pearson Prentice Hall, Inc. 16_34_Ras_transmits.jpg

33. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling Enzyme Linked Receptors Some activate fast track to the nucleus –Cytokines & a few hormones –JAK-STAT Pathway Receptor kinase activation => activation & translocation to nucleus of latent gene regulatory proteins held at plasma membrane F16-36 –SMAD Pathway F16-37 RTKs of the TGF-b superfamily –important in animal development –Auto phosphorylation => recruits & activates a SMAD, which releases, binds a different SMAD, move to nucleus & takes part in regulating gene activity

34. Copyright © 2005 Pearson Prentice Hall, Inc. 16_36_Cytokine_recpt.jpg

35. Copyright © 2005 Pearson Prentice Hall, Inc. 16_37_TGF_B_receptor.jpg

36. Copyright © 2005 Pearson Prentice Hall, Inc. Cell Signaling SIGNALING PATHWAYS CAN BE HIGHLY INTERCONNECTED F16-38 (like nerve networks in brain or microprocessors in a computer) “... a major challenge to figure out how cell communication pieces fit together to allow cells to integrate environmental signals and to respond appropriately”

37. Copyright © 2005 Pearson Prentice Hall, Inc. 16_38_Signal_pathways.jpg

38. Copyright © 2005 Pearson Prentice Hall, Inc. 16_39_integrate_signal.jpg