at the University of Pécs and at the University of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
INTRODUCTION PART 1
Tímea Berki and Ferenc Boldizsár Signal transduction
at the University of Pécs and at the University of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
History
• The earliest scientific paper recorded in the MEDLINE database as containing the specific term signal transduction within its text was published in 1972.
• Research papers directly addressing signal transduction processes began to appear in large numbers in the scientific literature in the late 1980s and early 1990s.
Year Number of papers published
2007 2002
1997 1992
1987 1982
1977 0 500 1 000 1 500 2 000 2 500 3 000 3 500 4 000
Signal transduction
• Signal transduction comes from the verb to 'transduce' meaning to 'lead across'
• In biology signal transduction is the process by
which an extracellular signaling molecule activates a membrane receptor that in turn alters intracellular molecules to create a response
• Sensing of both the external and internal
environments at the cellular level relies on signal
transduction
Cell communication pathways
The cells that are communicating might be close to each other or far apart:
• Local regulator: cytokines, chemokines
• Neurotransmission: Acetylcholine
• Hormone: steroid and peptide
Cells can also communicate through direct contact:
• Through a cell junction that allows cytoplasmic continuity
• Adhesion molecules
Cell communication pathways
Inducing stimulus
Cytokine producing cell
Cytokine
Receptor
Target cell
Biological effects
Nearby cell
Circulation
Distant cell Cytokine producing cell
Cytokine producing cell
Target cell
Autocrine action
Paracrine action
Endocrine action
Cytokine gene
Signal
Gene activation
Mechanisms of cytokine action
Redundancy
The action of more cytokine on the target cell is similar
Synergy
The effect of two cytokines is stronger than their additive effects
Antagonism
One cytokine inhibits the effects of another cytokine
Pleiotropy
A cytokine induces different effects on different target cells
Effect Target cell
Activation Proliferation Differentiation
Proliferation
INF-g
IL-12
INF-g, TNF, IL-2 and other cytokines IL-4
IL-2 IL-4 IL-5
IL-4 + IL-5
IL-4 INF-g
Starting a cascade Cytokine producing cell
Proliferation
Mast cell B cell
Thymocyte Activated Th cells
Proliferation
B cell Activated Th cells
Blocks class switch to IgE induced by IL-4
B cell Activated Th cells
Induces class switch to IgE
B cell Activated Th cells
Activated Th cells
Macrophage
Activated Th cells
Extracellular signaling molecules
• Hormones (e.g., melatonin)
• Growth factors (e.g., epidermal growth factor)
• Extracellular matrix components (e.g., fibronectin)
• Cytokines (e.g., interferon-g)
• Chemokines (e.g., RANTES)
• Neurotransmitters (e.g., acetylcholine, neuropeptides:
endorphin, small molecules: serotonine, dopamine)
• Neurotrophins (e.g., nerve growth factor)
• Active oxygen species and other electronically-activated compounds
Three stages of cell signaling
Reception
• Binding of messengers (ligand) to the receptors
• Receptor activation, changes in conformation, triggers a cascade Transduction
• Activation of other proteins through protein phosphorylation:
– Protein kinase
– Protein phosphatase
• Second messengers:
– Cyclic AMP
– Calcium ions/Inositol Triphosphate Response
Characteristics of the response
• Eventually, the signal creates a change in the cell, either in the expression of the DNA in the nucleus or in the activity of enzymes in the cytoplasm, rearrenging the cytoskeleton etc.
• These processes can take milliseconds (for ion flux),
minutes (for protein- and lipid-mediated kinase cascades), hours, or days (for gene expression).
• There is usually an amplification of the signal - one hormone can elicit the response of over 108 molecules
• Many disease processes, such as diabetes, heart disease, autoimmunity, and cancer arise from defects in signal
transduction pathways, further highlighting the critical importance of signal transduction to biology, as well as medicine.
Cytoplasm Outside of cell
Apolar signal
Receptor
Polar signal
Membrane bound receptor Cell membrane
Inside of cell
Main types of receptors
Types of cell-surface receptors
• Ligand-gated ion channels: e.g. acetylcholine receptor
• G-protein-linked receptors: guanyl nucleotide binding
proteins (G proteins) act as molecular switches; active when GTP is bound, inactive with GDP due to action of intrinsic GTPase – muscarinic AchR
• Enzyme-linked receptors: e.g. insulin receptor, T cell receptor
• Integrins
• Toll-like receptors
Ions
Signal molecule
Cytoplasm
Plasma membrane
Ligand-gated ion channels
GDP b g a
GTP b g a
b g
Enzyme Enzyme Enzyme
GTP a Signal molecule
G-protein Activated G-protein Activated enzyme
7-Transmembrane receptors
Mechanism of neurotransmission
• Synaptic vesicles contain a neurotransmitter (NT) and release it when their membranes fuse with the outer cell membrane
• Neurotransmitter molecules cross the synaptic cleft and bind to receptors known as ligand-gated ion channels (LGICs)
and G-protein–coupled receptors (GPCRs) on the postsynaptic neuron
• GPCRs on the presynaptic neuron’s axon terminal alter the function of voltage-gated ion channels and modulate
neurotransmitter release
• Neurotransmitter transporters remove neurotransmitter molecules from the synaptic cleft so that they can be repackaged into vesicles
Presynaptic neuron (axon terminal)
Postsynaptic neuron
Neurotransmitter molecule
NT transporter
Synaptic vesicles
Voltage-gated sodium channel
GPCR (modulatory)
Ligand-gated ion channel (direct excitation
or inhibition) +
+
neurotransmission
Enzyme
Signal molecule
Activated enzyme Dimer of signal molecule
Inactive catalytic domain
Active catalytic domain
