Title: Cell signalling
1Cell signalling
2Overview
- 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.
3- 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.
4- Eukaryotic microorganisms
- Pheromones coordinate
- Sexual mating
- Differentiation
- Plants, animals
- Extracellular signaling controls
- Metabolic processes
- Growth and differentiation
- Protein synthesis
5- Signal molecules produce responses in target
cells that have receptors. - In multicellular organisms
- Chemicals
- Small molecules (aa., lipid derivatives)
- Peptides
- proteins
- Some diffuse and bind to intracellular receptors
- Steroids, retinoids, thyroxine
6Cell signaling pathways
7Signal transduction
- Overall processes converting a signal into
cellular responses
8Cell Signaling
- Steps involved are
- 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)
9- 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
10Three types of signaling in animals
- Endocrine
- hormones
- Paracrine
- Neurotransmitters
- Growth factors
- Autocrine
- Growth factors (cultured cells, tumor cells)
11Ligand 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
12- 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)
13Intracellular 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
14Regulation of signaling
- External signal decreases
- Degradation of second mesenger
- Desensitization to prolonged signaling
- Receptor endocytosis
- Modulation of receptor activity
- Phosphorylation
- Binding to other proteins
15Receptors
16Hormones 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
17Classification 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.
18Hormones bind to intracellular receptors and to
cell-surface receptors
19Nitric oxide
20Intracellular 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.
21(No Transcript)
22Sequence 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.
23The intracellular receptor superfamily.
24Nuclear 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
25(No Transcript)
26- 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 RXR-VDR) - The specifity of the binding is determined by the
spacing between repeats.
27Regulation of transcription activity
- Regulatory mechanisms differ for hetero-dimeric
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
28- 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
29(No Transcript)
30Early primary response (A) and delayed secondary
response (B) that result from the activation of
an intracellular receptor protein.