Cell signalling
26 March 2007
Overview
• No cell lives in isolation
• In all multicellular organisms, survival depends on an
elaborate intercellular communication network that
coordinates the growth, differentiation, and metabolism
of the multitude of cells in diverse tissues and organs.
• Errors in cellular information processing are responsible
for diseases such as cancer, autoimmunity, and diabetes.
By understanding cell signaling, diseases can be treated
effectively and, theoretically, artificial tissues could be
built.
• Cells within small groups often communicate by direct
cell-cell contact. Specialized junctions in the plasma
membranes of adjacent cells permit them to exchange
small molecules and to coordinate metabolic responses;
other junctions between adjacent cells determine the
shape and rigidity of many tissues.
• In addition, the establishment of specific cell-cell
interactions between different types of cells is a
necessary step in the development of many tissues. In
some cases a particular protein on one cell binds to a
receptor protein on the surface of an adjacent target
cell, triggering its differentiation.
• Eukaryotic microorganisms
– Pheromones coordinate
• Sexual mating
• Differentiation
• Plants, animals
– Extracellular signaling controls
• Metabolic processes
• Growth and differentiation
• Protein synthesis
• Signal molecules produce responses in
target cells that have receptors.
• In multicellular organisms
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Chemicals
Small molecules (aa., lipid derivatives)
Peptides
proteins
• Some diffuse and bind to intracellular
receptors
– Steroids, retinoids, thyroxine
Cell signaling pathways
Signal transduction
– Overall processes converting a signal into
cellular responses
Cell Signaling
• Steps involved are:
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Synthesis
Release from signaling cells
Transport to target cells
Binding to receptor and activation
Signal transduction by activated receptor
Specific changes
Removal of signal (termination)
• Receptor activation
– Secreted or membrane bound molecules
• Hormones, growth factors, neurotransmitters,
pheromones
– Changes in the concentration of metabolites
• Oxygen or nutrients
– Physical stimuli
• Light, touch, heat
Three types of signaling in
animals
– Endocrine
• hormones
– Paracrine
• Neurotransmitters
• Growth factors
– Autocrine
• Growth factors
(cultured cells, tumor
cells)
Ligand binding and effector specificity
• Each receptor binds only a single ligand
or a group of closely related molecules.
However, many signaling molecules bind
to multiple types of receptors
• Acetylcholine binds to different receptors
on muscle cells (contraction), heart
muscle cells (inhibition of contraction)
and pancreas acinar cells (exocytosis of
secretory granules), respectively
• Different receptors of the same class that
bind different ligands generate the same
cellular response
• In liver, ACTH, epinephrine and glucagon
bind to different GPCRs; but all three
activate the same signaling pathway
(cAMP)
Intracellular signal transduction
• Many receptors transmit signals via
second messengers
• They rapidly alter the activity of enzymes
or non-enzymatic proteins
– Ca2+ triggers contraction in muscle cells
– Exocytosis of secretory vesicles in endocrine
cells
– cAMP generates different metabolic changes
in different type of cells
Regulation of signaling
• External signal decreases
– Degradation of second mesenger
• Desensitization to prolonged signaling
– Receptor endocytosis
• Modulation of receptor activity
– Phosphorylation
– Binding to other proteins
Receptors
Hormones Can Be Classified Based on
Their Solubility and Receptor Location
• Most hormones fall into three broad
categories:
• (1) small lipophilic molecules that diffuse
across the plasma membrane and interact
with intracellular receptors;
• (2) hydrophilic or (3) lipophilic molecules
that bind to cell-surface receptors.
• Recently, nitric oxide, a gas, has been
shown to be a key regulator controlling
many cellular responses
Classification of receptors
• Intracellular receptors (for lipid soluble
messengers)
• function in the nucleus as transcription factors to
alter the rate of transcription of particular genes.
• Plasma membrane receptors (for lipid
insoluble messengers)
• Receptors function as ion channels
• receptors function as enzymes or are closely
associated with cytoplasmic enzymes
• receptors that activate G proteins which in turn act
upon effector proteins, either ion channels or
enzymes, in the plasma membrane.
Hormones bind to intracellular
receptors and to cell-surface receptors
Nitric oxide
Intracellular Receptors
• Extracellular signal molecules are small,
lipid-soluble hormones such as steroid
hormones, retinoids, thyroid hormones,
Vitamin D. (Made from cholesterol)
• These hormones diffuse through plasma and
nuclear membranes and interact directly
with the transcription factors they control.
Sequence similarities and three functional regions
– N-terminal region of variable length (100-500 aa); in some
receptors portions of this region act as activation domain
– At the center, DNA binding domain, made of a repeat of C4-zinc
finger motif
– Near the C-terminal end, an hormone binding domain, which may
act as an activation or repression domain.
The intracellular receptor superfamily.
Nuclear receptor response elements
• Some characteristic sites of DNA are called
response elements and can bind several nuclear
receptors.
• These repeat regions are arranged either as an
invert repeat, or direct repeat.
– Inverted repeat: glucocorticoid response element;
estrogen response element
• Repeats are separated by any three bases, implicating
symmetrical binding of the receptor homodimer to DNA
• Receptors for vitaminD, retinoic acid and
thyroid hormone bind to direct repeats as
heterodimers,
• Second component of the heterdimer is
RXR monomer (i.e, RXR-RAR; RXRVDR)
• The specifity of the binding is determined
by the spacing between repeats.
Regulation of transcription activity
• Regulatory mechanisms differ for heterodimeric and homodimeric receptors
• Heterodimeric receptors are exclusively
nuclear; without ligand, they repress
transcription by binding to their cognate
sites in DNA
– They do so by histone deacetylation
• Homodimeric receptors are cytoplasmic in the
absence of ligands.
• Hormone binding leads to nuclear translocation
of receptors
• Absence of hormone causes the aggregation of
receptor as a complex with inhibitor proteins,
such as Hsp90
Early primary response (A) and delayed secondary response (B) that
result from the activation of an intracellular receptor protein.