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BCB 570 "Signal Transduction" 4/8/08
Drena Dobbs, ISU 1
for BCB 570 4/8/08 - Drena Dobbs ISU 1Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
One Biologist’s Perspective
Drena DobbsBCB & GDCB
Iowa State University
Signal Transduction
for BCB 570 4/8/08 - Drena Dobbs ISU 2Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Thanks to:
Howard Booth
BiologyEastern Michigan University
forSlides modified from his lecture
• Cell-Cell Communication
Marit Nilsen-Hamilton
BBMBIowa State University
forSlides copied from her lectures
• Small G proteins• GPCRs
for BCB 570 4/8/08 - Drena Dobbs ISU 3Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
An Aging Biologist’s
Perspective
Signal Transduction
for BCB 570 4/8/08 - Drena Dobbs ISU 4Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
The Perspective ofA Biologist
Signal Transduction
Who Studies Aging
for BCB 570 4/8/08 - Drena Dobbs ISU 5Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Greer, E. L. et al. J Cell Sci 2008;121:407-412 for BCB 570 4/8/08 - Drena Dobbs ISU 6Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
The Perspective ofA Biologist
Who Studies G-proteins
Signal Transduction
BCB 570 "Signal Transduction" 4/8/08
Drena Dobbs, ISU 2
for BCB 570 4/8/08 - Drena Dobbs ISU 7Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Buchsbaum, R. J. J Cell Sci 2007;120:1149-1152 for BCB 570 4/8/08 - Drena Dobbs ISU 8Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Schwartz, S. L. et al. J Cell Sci 2007;120:3905-3910
for BCB 570 4/8/08 - Drena Dobbs ISU 9Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
1. Why is Signal Transduction so important?
2. What are Components of Signal Transduction 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
3. How is Signal Transduction Studied (Experimentally)?for BCB 570 4/8/08 - Drena Dobbs ISU 10
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Watch: Inner Life of a Cell
• Go to U-Tube!! - or better, HARVARD:
• http://multimedia.mcb.harvard.edu/media.html
• http://www.studiodaily.com/main/technique/tprojects/6850.html
Leukocytes = White blood cells Function in immunity
for BCB 570 4/8/08 - Drena Dobbs ISU 11Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
A few URLs: the tip of an iceberg! - p. 1
Kimballs’ Biology Pages - Glossary, Notes, etc:http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/
Cell Signaling:http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellSignaling.htmlhttp://www.biochemweb.org/signaling.shtml
Hormones in Humans:http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/H/Hormones.html
for BCB 570 4/8/08 - Drena Dobbs ISU 12Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
A few URLs: the tip of an iceberg! - p. 2
Cytokines & Cytokine Receptors:http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellSignaling.html#Cytokine_Receptors
GPCRs:http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellSignaling.html#GPCRs
G-proteins: http://www.webbooks.com/MoBio/Free/Ch6D2.htmhttp://users.rcn.com/jkimball.ma.ultranet/BiologyPages/G/G_Proteins.html
p53: http://www.webbooks.com/MoBio/Free/Ch4Hp53.htm
ATPases: http://multimedia.mcb.harvard.edu/media.html
BCB 570 "Signal Transduction" 4/8/08
Drena Dobbs, ISU 3
for BCB 570 4/8/08 - Drena Dobbs ISU 13Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
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 withreceptors on nearby cellsEx: 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 andresponds toAutocrine signaling can occur:
• Solely within the cytoplasm of the cell• By secreted chemical interacting with receptors on surface of same cell
for BCB 570 4/8/08 - Drena Dobbs ISU 14Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
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
for BCB 570 4/8/08 - Drena Dobbs ISU 15Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Cytokine Receptors
Dozens of cytokine receptors have been discoveredMost fall into one of several major families:
1. Receptor Tyrosine Kinases (RTKs)2. TNF (tumor necrosis factor) superfamily receptors3. 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 pathwaysJAK-STAT signaling mediates cellular responses to cytokines and growth factors. EmployingJanus kinases (JAKs) and Signal Transducers & Activators of Transcription (STATs), the pathwaytransduces the signal carried by these extracellular polypeptides to the cell nucleus, whereactivated STAT proteins modify gene expression <Wikipedia>
for BCB 570 4/8/08 - Drena Dobbs ISU 16Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Review a few topics:
• How cells communicate• Electrical and chemical signals• Receptor types and how they function• Local regulation of cells
for BCB 570 4/8/08 - Drena Dobbs ISU 17Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
• Chemical• Autocrine & Paracrine: local signaling
• via cytokines. neurotransmitters
• Endocrine: distant targets• via hormones
• Electrical• Nervous system: fast, specific, distant target• Gap junctions: local
Types of Cell to Cell Communication:
for BCB 570 4/8/08 - Drena Dobbs ISU 18Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
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 communicationCopyright © 2004 Pearson Education, Inc., pub as Benjamin Cummings
BCB 570 "Signal Transduction" 4/8/08
Drena Dobbs, ISU 4
for BCB 570 4/8/08 - Drena Dobbs ISU 19Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Paracrine & Autocrine Signaling
• Local communication• Signals diffuse to targets• Ex: Cytokines
• Autocrine– receptor onsame cell
• Paracrine – neighboringcells
Figure 6-1c: Direct and local cell-to-cell communicationCopyright © 2004 Pearson Education, Inc., pub as Benjamin Cummings for BCB 570 4/8/08 - Drena Dobbs ISU 20
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
• Made in endocrine cells• Transported via blood• Receptors on target cells
Long Distance Communication: Endocrine Signaling - via Hormones
Figure 6-2a: Long distance cell-to-cell communicationCopyright © 2004 Pearson Education, Inc., pub as Benjamin Cummings
for BCB 570 4/8/08 - Drena Dobbs ISU 21Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
• 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 classicalneurotransmitters as it can have effects on cells distant from the source of thehormone. Examples?
• GnRH = Gonadotropin releasing hormone• CRH = Corticotropin releasing hormone• TRH = Thyrotropin-releasing hormone• Dopamine• Prolactin inhibiting hormone• Orexin (aka hypocretin) <Wikipedia>
Long Distance Communication: Neurons and Neurohormones
for BCB 570 4/8/08 - Drena Dobbs ISU 22Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Long Distance Communication: Neurons and Neurohormones
Figure 6-2b, c: Long distance cell-to-cell communicationFigure 6-2 b: Long distance cell-to-cell communication
Copyright © 2004 Pearson Education, Inc., pub as Benjamin Cummings
for BCB 570 4/8/08 - Drena Dobbs ISU 23Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Summary: Components of Signaling Pathways
• Extracellular signaling molecule (cytokine, hormone)
• Receptor• Intracellular signaling molecule
(kinase, second messenger)
• Target protein (kinase, transcription factor)
• Response
Figure 6-3: Signal pathwaysCopyright © 2004 Pearson Education, Inc., pub as Benjamin Cummings for BCB 570 4/8/08 - Drena Dobbs ISU 24
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Receptor locations?
• Intracellular:• Cytosolic or Nuclear• Lipophilic ligand enters cell• Often activates transcription
of gene(s)• Relatively slow response
• Cell surface:• Transmembrane• Lipophobic ligand can't enter
cell• Often activates protein
kinase cascade• Relatively fast response
Figure 6-4: Target cell receptorsCopyright © 2004 Pearson Education, Inc., pub as Benjamin Cummings
BCB 570 "Signal Transduction" 4/8/08
Drena Dobbs, ISU 5
for BCB 570 4/8/08 - Drena Dobbs ISU 25Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
• 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)
Membrane Receptor Classes
for BCB 570 4/8/08 - Drena Dobbs ISU 26Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Membrane Receptor Classes
Figure 6-5: Four classes of membrane receptors
Copyright © 2004 Pearson Education, Inc., pub as Benjamin Cummings
for BCB 570 4/8/08 - Drena Dobbs ISU 27Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Receptor Enzyme: ReceptorTyrosine Kinase• Transmembrane (TM)
proteins• Transduce signal across
membrane• Binding of ligand to
extracellular receptordomain
• Somehow transducessignal through TMdomain
• Resulting in activationof intracellular kinasedomain
Figure 6-10: Tyrosine kinase, an example of a receptor-enzymeCopyright © 2004 Pearson Education, Inc., pub as Benjamin Cummings for BCB 570 4/8/08 - Drena Dobbs ISU 28
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
G Protein-Coupled Receptors = GPCRs
Figure 6-11: The G protein-coupled adenylyl cyclase-cAMP systemCopyright © 2004 Pearson Education, Inc., pub as Benjamin Cummings
for BCB 570 4/8/08 - Drena Dobbs ISU 29Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
G Protein-Coupled Receptors
• 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???
for BCB 570 4/8/08 - Drena Dobbs ISU 30Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Summary: Steps in Signal Transduction
• Signal = ligand (small molecule)• Binds Receptor, which activates:• Protein kinases
• Tyr or Ser/Thr• & Second messengers
• cAMP, Ca++, DAG, which result inactivation of “downstream”proteins or enzymes via:
• Phosphorylation cascades or otherpost-translational modifications(PTMs) or Ca++ binding
• Resulting in Cellular Response
Figure 6-8: Biological signal transductionCopyright © 2004 Pearson Education, Inc., pub as Benjamin Cummings
BCB 570 "Signal Transduction" 4/8/08
Drena Dobbs, ISU 6
for BCB 570 4/8/08 - Drena Dobbs ISU 31Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Ca++ - Mediated Signaling?
Figure 6-15: Calcium as an intracellular messenger
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
Copyright © 2004 Pearson Education, Inc., pub as Benjamin Cummings for BCB 570 4/8/08 - Drena Dobbs ISU 32Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Critical Aspect: Signal Amplification
• Small signal produceslarge cellular response
• via amplification enzymes• Ex: “phosphorylation” or
“kinase” cascade( MAP kinase cascade)
Figure 6-7: Signal amplificationCopyright © 2004 Pearson Education, Inc., pub as Benjamin Cummings
for BCB 570 4/8/08 - Drena Dobbs ISU 33Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Signal Transduction: the Big Picture
Copyright © 2004 Pearson Education, Inc., pub as Benjamin CummingsFig 6-14: Summary of signal transduction systems
for BCB 570 4/8/08 - Drena Dobbs ISU 34Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Take home messages:1. Signal Transduction involves transfer of signal
information, often from outside a cell (environmentalstimulus) to inside, evoking a response
Extracellular Signal >>> Cellular Response2. Amplification of signal occurs via activation of kinases
(“kinase cascades”) or release of Ca++ (Ca++ -mediatedsignaling)
3. In eukaryotic cells, membranes and membranouscompartments (nucleus, ER, Golgi apparatus, plasmamembrane) play critical roles in signal transduction
4. Cross-talk occurs between components of differentsignal transduction pathways/networks
for BCB 570 4/8/08 - Drena Dobbs ISU 35Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Signal Transduction & Cancer:
1. Cancer is a genetic disease (although only a few raretypes of cancer are known to be inherited)
2. Most of what we know about cancer - and about normaldevelopment - was built on results of basic biologicalresearch 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” cellulargenes that have been “picked up” by viruses
for BCB 570 4/8/08 - Drena Dobbs ISU 36Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
HPV, Vaccines & Cancer1. Cervical cancer (a deadly cancer in women) is caused by
certain strains of Human Papilloma Virus (HPV), forwhich a vaccine is now available
2. Many health insurance policies do not cover the cost ofGardasil (but do cover the cost of Viagra…)
3. HPV is sexually-transmitted4. Both men & women can be infected with no obvious
symptoms5. ~75% of US reproductive-age population has been
infected with one or more types of genital HPV6. HPV also causes certain cancers in men (~10% as
frequent as cervical cancer in women)http://www.cdc.gov/std/HPV/default.htm#fact