Thanks to: Signal Transduction. BCB 570 "Signal Transduction" 4/8/08. Drena Dobbs, ISU 1. An Aging Biologist s. One Biologist s Perspective

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1 BCB 570 "" Thanks to: One Biologist s Perspective Drena Dobbs BCB & GDCB Iowa State University Howard Booth Biology Eastern Michigan University for Slides modified from his lecture Cell-Cell Communication Marit Nilsen-Hamilton BBMB Iowa State University for Slides copied from her lectures Small G proteins GPCRs 1 2 An Aging Biologist s Perspective The Perspective of A Biologist Who Studies Aging 3 4 The Perspective of A Biologist Who Studies G-proteins for Greer, BCB 570 E. L. et al. J - Cell Drena Sci Dobbs 2008;121: ISU 5 6 Drena Dobbs, ISU 1

2 BCB 570 "" Buchsbaum, for BCB 570 R. J. J Cell - Drena Sci 2007;120: Dobbs ISU 7 Schwartz, for BCBS.570 L. et al. J Cell - Drena Sci 2007;120: Dobbs ISU 8 Watch: Inner Life of a Cell 1. Why is so important? 2. What are Components of Pathways? Cytokines & Cytokine Receptors (e.g. Ig-superfamily Receptors) Hormones & Hormone Receptors (e.g., GPCRs) G-Proteins Small G-proteins (e.g., Ras, Rab, Rho) Heterotrimeric G-proteins Second Messengers (e.g., Ca++, camp, DAG) Kinases & Phosphatases Transcription Regulatory Factors and Co-factors (RF&CFs) Post-transcriptional RF&CFs Translational RF&CFs Post-translational RF&CFs Metabolic RF&CFs Go to U-Tube!! - or better, HARVARD: html Leukocytes = White blood cells Function in immunity 3. How is Studied (Experimentally)? 9 A few URLs: the tip of an iceberg! - p A few URLs: the tip of an iceberg! - p. 2 Cytokines & Cytokine Receptors: Kimballs Biology Pages - Glossary, Notes, etc: ml#cytokine_receptors Cell Signaling: GPCRs: ml#gpcrs G-proteins: Hormones in Humans: p53: ATPases: Drena Dobbs, ISU

3 BCB 570 "" Endocrinology = re: Hormones 3 basic types of chemical signaling: Endocrine - cell secretes chemicals that are carried by blood or tissue fluids to distant cells upon which they act Ex: Release of Hormones (which can be proteins, peptides, steroids) Paracrine - cell releases chemical signals that diffuse and interact with receptors on nearby cells Ex: Release of Cytokines that cause an inflammatory response Release of Neurotransmitters at synapses in the nervous system Autocrine - cell signals itself with a chemical that it both synthesizes and responds to Autocrine signaling can occur: Solely within the cytoplasm of the cell By secreted chemical interacting with receptors on surface of same cell Cytokines What are cytokines? Cell signaling molecules secreted by a cell, which: signal other cells in a paracrine fashion or signal the secreting cell (in an autocrine fashion) Play important roles in immunity Structurally diverse; mainly small 8-30 kda, water-soluble proteins & glycoproteins Ex: various lymphokines, chemokines, interleukins What are other types of cell signaling molecules? Hormones, Growth Factors, Neurotransmitters Cytokine Receptors Review a few topics: Dozens of cytokine receptors have been discovered Most fall into one of several major families: 1. Receptor Tyrosine Kinases (RTKs) 2. TNF (tumor necrosis factor) superfamily receptors 3. TGF-β (transforming growth factor) receptors (Ser/Thr Kinases) 4. Immunoglobulin superfamily receptors (IgRs) 5. Chemokine receptors (e.g., GPCRs) 6. Type I/II cytokine receptors that trigger JAK-STAT pathways JAK-STAT signaling mediates cellular responses to cytokines and growth factors. Employing Janus kinases (JAKs) and Signal Transducers & Activators of Transcription (STATs), the pathway transduces the signal carried by these extracellular polypeptides to the cell nucleus, where activated STAT proteins modify gene expression <Wikipedia> How cells communicate Electrical and chemical signals Receptor types and how they function Local regulation of cells Types of Cell to Cell Communication: Chemical Autocrine & Paracrine: local signaling via cytokines. neurotransmitters Endocrine: distant targets via hormones Electrical Nervous system: fast, specific, distant target Gap junctions: local Gap Junctions and CAMs Protein channels - connexins Direct flow to neighbor Electrical - ions (charge) Chemicals/proteins CAMs - Cell Adhesion Molecules Need direct surface contact Chemicals/proteins Figure 6-1a, b: Direct and local cell-to-cell communication Drena Dobbs, ISU 3

4 BCB 570 "" Long Distance Communication: Endocrine Signaling - via Hormones Paracrine & Autocrine Signaling Local communication Made in endocrine cells Signals diffuse to targets Transported via blood Ex: Cytokines Receptors on target cells Autocrine receptor on same cell Paracrine neighboring cells Figure 6-2a: Long distance cell-to-cell communication Figure 6-1c: Direct and local cell-to-cell communication 19 Long Distance Communication: Neurons and Neurohormones 20 Long Distance Communication: Neurons and Neurohormones Neurons Electrical signal travels down axon (can be very long!!) Change in potential causes release (in synapse) of neurotransmitters that bind to receptors on nearby target cell Neurohormones Hormones transported via blood to target A neurohormone is any hormone produced by neurosecretory cells, usually in the brain. Neurohormonal activity is distinguished from that of classical neurotransmitters as it can have effects on cells distant from the source of the hormone. Examples? GnRH = Gonadotropin releasing hormone CRH = Corticotropin releasing hormone TRH = Thyrotropin-releasing hormone Dopamine Prolactin inhibiting hormone Orexin (aka hypocretin) <Wikipedia> Figure 6-2b, c: Long distance cell-to-cell communication Figure 6-2 b: Long distance cell-to-cell communication 21 Summary: Components of Signaling Pathways Intracellular: Cytosolic or Nuclear Lipophilic ligand enters cell Often activates transcription of gene(s) Relatively slow response (cytokine, hormone) Receptor Intracellular signaling molecule (kinase, second messenger) Target protein Cell surface: (kinase, transcription factor) Transmembrane Lipophobic ligand can't enter cell Often activates protein kinase cascade Relatively fast response Response Figure 6-3: Signal pathways Drena Dobbs, ISU Receptor locations? Extracellular signaling molecule Figure 6-4: Target cell receptors 23 4

5 BCB 570 "" Membrane Receptor Classes Membrane Receptor Classes Integrins (in Inner Life of Cell) Ligand-gated channels Receptor enzymes RTKs & other single pass transmembrane (TM) domain receptors G-protein coupled GPCRs & other 7 TM domain receptors) Figure 6-5: Four classes of membrane receptors Receptor Enzyme: ReceptorTyrosine Kinase Transmembrane (TM) proteins Transduce signal across membrane Binding of ligand to extracellular receptor domain Somehow transduces signal through TM domain Resulting in activation of intracellular kinase domain G Protein-Coupled Receptors = GPCRs Figure 6-10: Tyrosine kinase, an example of a receptor-enzyme Figure 6-11: The G protein-coupled adenylyl cyclase-camp system 27 Copyright Copyright Pearson Pearson Education, Education, Inc., Inc., pub publishing as Benjamin as Cummings Benjamin Cummings 28 G Protein-Coupled Receptors Summary: Steps in Hundreds of types Main signal transducers in eukaryotic cells Activate enzymes Open ion channels (e.g., to allow influx of Ca ++ ) Amplify signals: Adenyl cyclase >>> camp Activate downstream effectors Effector? Protein/enzyme activated by another protein But - What is a G-protein??? Signal = ligand (small molecule) Binds Receptor, which activates: Protein kinases Tyr or Ser/Thr & Second messengers camp, Ca ++, DAG, which result in activation of downstream proteins or enzymes via: Phosphorylation cascades or other post-translational modifications (PTMs) or Ca ++ binding Resulting in Cellular Response 29 Figure 6-8: Biological signal transduction 30 Drena Dobbs, ISU 5

6 BCB 570 "" Ca ++ - Mediated Signaling? Critical Aspect: Signal Amplification In neurons: Electrical signal causes: Ca ++ release from intracellular stores (endoplasmic reticulum, ER) or Influx of Ca ++ through voltage-gated Ca ++ channels Activates Ca ++ binding proteins Causing conformational changes that Activate downstream effectors Small signal produces large cellular response via amplification enzymes Ex: phosphorylation or kinase cascade ( MAP kinase cascade) Figure 6-15: Calcium as an intracellular messenger Figure 6-7: Signal amplification 31 Copyright Copyright Pearson Pearson Education, Education, Inc., Inc., pub publishing as Benjamin as Cummings Benjamin Cummings 32 : the Big Picture Take home messages: 1. involves transfer of signal information, often from outside a cell (environmental stimulus) to inside, evoking a response Extracellular Signal >>> Cellular Response 2. Amplification of signal occurs via activation of kinases ( kinase cascades ) or release of Ca ++ (Ca ++ -mediated signaling) 3. In eukaryotic cells, membranes and membranous compartments (nucleus, ER, Golgi apparatus, plasma membrane) play critical roles in signal transduction 4. Cross-talk occurs between components of different signal transduction pathways/networks Fig 6-14: Summary of signal transduction systems & Cancer: 1. Cancer is a genetic disease (although only a few rare types of cancer are known to be inherited) 2. Most of what we know about cancer - and about normal development - was built on results of basic biological research on rare cancer-causing viruses 3. Such studies have shown that: All known cancers result from mutations in components of signal transduction networks (& genes that control cell division or DNA repair) Viral oncogenes are variants of normal cellular genes that have been picked up by viruses HPV, Vaccines & Cancer 1. Cervical cancer (a deadly cancer in women) is caused by certain strains of Human Papilloma Virus (HPV), for which a vaccine is now available 2. Many health insurance policies do not cover the cost of Gardasil (but do cover the cost of Viagra ) 3. HPV is sexually-transmitted 4. Both men & women can be infected with no obvious symptoms 5. ~75% of US reproductive-age population has been infected with one or more types of genital HPV 6. HPV also causes certain cancers in men (~10% as frequent as cervical cancer in women) Drena Dobbs, ISU 6