MICR 304 Immunology & Serology
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Transcript of MICR 304 Immunology & Serology
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MICR 304 Immunology &
Serology
MICR 304 Immunology &
Serology
Lecture 7A Signal Transduction
Chapter 6.1 –6.9, 6.12-6.16
Lecture 7A Signal Transduction
Chapter 6.1 –6.9, 6.12-6.16
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Overview of Today’s Lecture
• Principles of signal transduction• Structure of signal transducing
receptors• Membrane properties in regions
with signal transduction• Major signal transducing pathways
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Signal Transduction
• Transmembrane receptors convert extracellular signals to intracellular biochemical events
• Surface receptors with signaling functions are either transmembrane proteins or associate with transmembrane proteins
• Ligand binding and receptor clustering trigger enzymatic activity– Protein kinases are most commonly activated
…CTWAEPYCH….
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Protein Phosphorylation• Addition of phosphate group to an
amino acid by kinases– Tyrosine in early activation events– Serine and threonine in later events
• Kinase can be part of receptor or can be associated with receptor
• Enzyme activation• Creation of binding sites for other
proteins (adaptor proteins)• Quick• Reversible through phosphatases
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Kinase Activity of Signal Transducing Receptors
Kinase domain is intrinsic part of receptor
e.g., many growth factors
Kinase is non-covalently associated with receptor
e.g., antigen receptor, many cytokine receptors
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Receptor Clustering
Membrane is rich in cholesterol and saturated phospholipids
• Kinase activation upon receptor clustering• Occurs in special membrane region called lipid rafts
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Propagation of Signals by Assembly of Signaling
Complexes
• Creates large multiprotein signaling complexes
• Involves protein interaction domains
• Scaffold and adaptor proteins are used– Do not have enzymatic activity– Recruit other proteins to a signaling
complex
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Propagation of Signal through Scaffolds
• Larger unphosphorylated proteins• Tyrosine phosphorylation on multiple sites• Recruit many different proteins
Scaffolds become tyrosine phosphorylated.
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Propagation of Signal throughAdaptor Proteins
• Smaller proteins• Link two signaling proteins together• Bind to phosphorylated tyrosin• 2 or 3 functional domains• SH2 domain is one of most important
domains– Src homology 2 domain– Binds to phosphotyrosine in a sequence
specific fashion
• SH3 domain binds to proline-rich motifs
PYXXZ
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Example for an Adaptor Protein
Adaptor proteins bind to phosphorylated proteins.
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Signaling Pathways Amplify the Initial Signal
• Activation of enzymes• Generation of small biochemical
mediators known as second messengers• One activated enzyme can produce
hundreds of second messengers
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Means of Signaling Pathway Amplification
Activation ofkinase cascade
Increase of intracellular Ca2+
Activation of downstream signaling molecules such as calmodulin
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Selected Common Signal Transduction Pathways
• Common in many cell types (not only lymphocytes)• Triggered by various stimuli through specific
receptors• Examples
– Src (sarc) tyrosine kinase family– Phospholipase C/protein kinase C amplification– Small G-proteins
Activation of transcription factors
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The src - Family of Tyrosine Kinases
• Receptor associated tyrosine kinases• Initial activation event• Add phosphate group to tyrosine residues• Src from “sarcoma”• Oncogene
– Viral gene that induces tumors
• Host has related genes involved in cell growth– Mutated genes in tumors
• Activate other signal transducing molecules– PLC, GEF
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Amplification of Signal via PLC/PKC
• Phospholipase C becomes phosphorylated• Catalyzes the break down of the membrane lipid
phosphatidylinositol biphosphate (PIP2) to inositol triphosphate (IP3, second messenger) and diacylglocerol (DAG, membrane lipid)
• IP3 increases intracellular calcium
• DAG and Ca2+ activate protein kinase C (serine/threonine kinase)
• Activation of three different transcription factors– NFkB (nuclear factor kappa B)– NFAT (nuclear factor of activated T cells)– AP-1
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Calcium Release Activated Calcium channels
Antigen Receptor
PLC
PIP2
DAG IP3
Protein Kinase CSmall G proteinMAP Kinases
Intracellular Ca2+Calcineurin
AP-1NFkB NFAT
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Small G-Protein Cascade
• Small GTP binding proteins– E.g. : Ras– Oncogene in tumor inducing viruses– Related genes in all eukaryotic cells– Mutant forms found in many tumors
• Are activated by GEF (Guanine-nucleotide Exchange Factor)
• Key components of several signaling pathways– MAP kinase pathway (Mitogen Activated
Protein kinases)
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Reversible Action of Small G-Proteins
Inactive(Off)
Active(On)
Inactive(Off)
Activation of MAP kinases
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MAP Kinase Activation Pathway
MAP Kinase
Activation of Transcription Factors
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Turning Off Signaling• Dephsophorylation• Ubiquitination
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Today’s Take Home Message• Signal transducing events commonly involve
phosphorylation cascades.
• Tyrosine kinases are important in early steps of cell activation, serine and threonine kinases are important in later steps of activation.
• Src kinase, small G proteins and MAP Kinases, and phospholipase C/Protein kinase C are common signal tranducing pathways.
• Amplification of the signals occurs through increase of intracellular calcium concentration.