Transcript CELL SIGNALLING

CELL SIGNALING
Lecture 1
Course Contents
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Overview of cell signaling
Principles of cell signaling
Types of ligands and receptors
Signaling through enzyme liked cell-surface receptors
Receptor tyrosine kinases and non-receptor tyrosine kinases
Signaling via receptor tyrosine kinases
Signaling via tyrosine kinase associated receptors
Signaling via receptor serine-/threonine kinases
Signaling through G protein linked receptors
– Small GTPases
– G protein coupled receptors
– Lipid (2nd messengers)-mediated cell signaling
• Synaptic signaling
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ATP-signaling
Purinergic (P2X and P2Y) signaling
iNOS signaling
Cell adhesion molecules
Plant cell signaling (role of growth factors, hormones and
pheromones)
• Plant defense mechanism
• Signaling in microbes
BOOKS RECOMMENDED
• Molecular Biology of the Cell by Bruce Albert and Dennis Bray, 4th
Ed. Garland Publishing Inc, New York and London
• Handbook of Cell Signaling Vol 1-3, by Ralph Bradshaw, and
Edward Dennis
• Signal Transduction by Bastien D. Gomperts
• The Biochemistry of Cell Signalling (Paperback)by Ernst J. M.
Helmreich
INTRODUCTION
• No cell lives in isolation
• Eukaryotic organisms like yeast and molds also secrete
molecules known as Pheromones
• Higher animals secrete extracellular molecules that
function within an organism
• Ligand
• Receptor
• The overall process of converting signals into cellular
responses as well as the individual steps in this process
is termed as SIGNAL TRANSDUCTION
GENERAL PRINCIPLES OF CELL
SIGNALING
Extracellular Signaling Molecules are
Recognized by Specific Receptors on or in
Targets Cells
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Cells in higher animals communicate through
hundreds of signalling molecules, including
Proteins
Small peptides
Amino acids
Nucleotides
Steroids
Retinoids
Fatty acids derivatives and even
Gases like nitric oxide and carbon monoxide
• Most of these molecules are secreted by
the signaling cell through
1. Exocytosis
2. Diffusion through plasma membrane, or
3. Remain tightly bound to the cell surface
• Regardless of the nature of the signaling
molecule, the target cell responds by means of a
specific protein known as the RECEPTOR
• Extracellular signaling molecules act at very low
concentrations ( < 10 -8 M)
• While the receptors that recognize them bind
them with very high affinity
• In most cases the receptors are transmembrane
proteins that upon activation trigger a cascade of
signaling events
• However some receptors lie inside the cell
• And the LIGAND needs to diffuse inside the cell
to activate it
• In these cases the ligand is usually a small and
hydrophobic molecule
Secreted Molecules Mediate 3 Forms of
Signaling
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Paracrine,
Synaptic and
Endocrine
• Type of signaling path mediated
depends upon the distance that the
signaling molecule is required to cover
Paracrine Signaling
• The secreted molecule must not be
allowed to diffuse too far
• Often rapidly taken up by target
neighboring cells
• Destroyed by extracellular enzymes, or
• Immobilized by extracellular matrix
Synaptic Signaling
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Sets of specialized cells have evolved with a
specific role in signaling between widely
separated parts of the body of complex
organisms
Most sophisticated are the nerve cells
Upon activation the signal is transmitted in the
form of action potential as an electrical impulse
At the nerve terminal a chemical signal
(neurotransmitter) is released
The signal is transmitted through special cell
junctions known as Chemical Synapses
Endocrine Signaling
• Another example of specialized cells
operating over a distance are endocrine
cells
• Secrete signaling molecules known as
HORMONES
• Into the blood stream (animals) or
• The sap (plants)
Contrast
• Endocrine signaling is slow since it relies on diffusion
and blood flow
• Nerve cells can achieve much higher speed and
precision
• 100 meters per second
• A neurotransmitter has to diffuse less than 100nm to the
target cell
• This process takes less than a millisecond
• Hormones are greatly diluted and act at very low
concentrations while neurotransmitters can achieve high
local concentrations
• Acetylcholine concentration at a synaptic cleft can reach
a conc. of 5 x 10 -4 M
• Correspondingly neurotransmitter receptors have low
affinity for their ligands as compared to hormones
Autocrine Signaling can Coordinate
Decisions by Groups of Identical Cells
• Cells not only communicate to other types of cells but
also to their own types
• And can also send signals to themselves
AUTOCRINE SIGNALING
• Thus a secreted molecule can bind receptors on the cell
itself
• When carried out simultaneously by neighboring cells,
autocrine signaling can direct cells to take the same
decision e.g during differentiation (developmental
decisions)
• Also known as COMMUNITY EFFECT
Eicosanoids are molecules secreted in mature mammals
• Are fatty acid derivatives
• There are four major classes of eicosanoids • prostaglandins, prostacyclins, thromboxanes,and leukotrienes
• Are continuously synthesized in the plasma membrane and
released to the cell exterior
• Where they are degraded by enzymes
Involved in various biological activities
• Contraction of smooth muscles
• Aggregation of platelets
• Pain and inflammatory responses
It has been observed that in case of tissue damage or any other
chemical signal the rate of eicosanoid synthesis increases
• Influencing both the synthesizing cell and also its neighbors
• The synthesis of all but the leukotrienes involves the enzyme
cyclooxygenase; the synthesis of leukotrienes involves the enzyme
lipoxygenase
• These synthetic pathways are targets for a large number of
therapeutic drugs, since eicosanoids play an important part in pain,
fever, and inflammation
• Corticosteroid hormones such as cortisone, which inhibit the
activity of the phospholipase in the first step of the eicosanoid
synthesis pathway, are widely used clinically to treat noninfectious
inflammatory diseases
• Nonsteroid anti-inflammatory drugs such as aspirin and ibuprofen,
by contrast, block the first oxidation step, which is catalyzed by
cyclooxygenase.
• Certain prostaglandins that are produced in large amounts in the
uterus at the time of childbirth to stimulate the contraction of the
uterine smooth muscle cells are widely used as pharmacological
agents to induce abortion.