introduction to signaling networks biophysics 702, february 2012 jonathan p butchar
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General Signaling ConceptsTRANSCRIPT
Introduction to Signaling Networks
Biophysics 702, February 2012Jonathan P Butchar
Intracellular and Intercellular signaling
• General Signaling Concepts• Types of Signaling• Initial Signaling Components
– Receptors– Ligands
• Downstream Signaling Components– Kinases– Phosphatases– Adaptors & Effectors
General Signaling Concepts
Figure 15-8 Molecular Biology of the Cell (© Garland Science 2008)
Signaling is multifaceted and dynamic
• Different outcomes, even from a single signal– e.g., Strength of signal
• Convergence of signals• Crosstalk between pathways• Cells can adapt over time
– dampened or heightened responses
• Signals can be amplified or dampened via feedback
• Primary versus secondary responses
Types of Signaling
Numerous ways to signal
• Contact-dependent• Autocrine / Paracrine• Endocrine• Direct Transmission (gap junctions)
Initial Signaling Components• Receptors and Ligands
Receptors
• Cell surface• Intracellular
Ligands
• Peptides / Proteins• Steroids• Nucleotides• Fatty Acids• Gases• Mechanical Forces• …etc
How are these signals transmitted?
• Ion fluxes• G-protein activation• Enzyme activation (e.g., Phosphorylation)
Figure 15-53a Molecular Biology of the Cell (© Garland Science 2008)
Example: Receptor Tyrosine Kinases
Downstream Signaling Components
• Kinases• Phosphatases• Adaptors• Effectors
What molecules transmit the signals?
• Kinases add phosphate groups• Phosphatases remove these phosphates• Guanosine Tri-Phosphate / GDi-P cycles
drive many signaling cascades• Adaptors help bring necessary molecules
together• Effectors generate the responses
– commonly gene transcription
Figure 15-18a Molecular Biology of the Cell (© Garland Science 2008)
Kinases and phosphatases
e.g., Receptor Tyrosine Kinase: a receptor AND a kinase
Figure 15-18b Molecular Biology of the Cell (© Garland Science 2008)
Guanosine TriPhosphate and Guanosine DiPhosphate
e.g., G-protein coupled receptor
Figure 15-32 Molecular Biology of the Cell (© Garland Science 2008)
Trimeric G-proteins
• 3 subunits– α, β, γ
…another view, from WikipediaActivated when GTP replaces GDP, inactivated when GTP is auto-hydrolyzed to GDP
Figure 15-19 Molecular Biology of the Cell (© Garland Science 2008)
Monomeric G-proteins
• Most well-known is Ras– small GTPase– downstream Raf binds
only GTP-Ras, which phosphorylates and hence activates Raf
GTPase-activating protein
Guanine nucleotide exchange factor
Figure 15-22 Molecular Biology of the Cell (© Garland Science 2008)
Adaptor and Scaffold proteins have characteristic domains
• SH2 binds phosphotyrosine
• SH3 binds proline-rich domains
• PH binds phosphoinositides
Proline-rich
How proper localization is achieved
• Association at plasma membrane• Scaffolding proteins• Direct receptor binding
Figure 15-36 Molecular Biology of the Cell (© Garland Science 2008)
Signaling Example: from G-proteins to gene
transcription
• Activated receptor• Activated G-protein• Activated Protein Kinase A• The Effector, an activated
transcriptional modulator
Lines are blurry at times
• Some membrane-bound receptors can go to the nucleus and regulate gene transcription– Both a receptor and an effector
• Phosphorylation can sometimes deactivate rather than activate a protein
Summary
• Cells and groups of cells possess mechanisms to generate and respond to signals
• Signaling can be autocrine, paracrine, endocrine, synaptic, electrical or mechanical
• Receptors sense numerous types of stimuli and begin cascades that lead to cellular responses
• Observed responses represent an integration of numerous stimuli, both past and present