Molecular Cell Biology
Prof. D. Karunagaran
Department of Biotechnology
Indian Institute of Technology Madras
Module 7
Cell Signaling Mechanisms
Lecture 1
Introduction to Signals and Signal Transduction
Signal transduction
Responding to a signal from the environment (intracellular or extra cellular) is
a fundamental character of all living cells or organisms.
Bacteria respond to changes in oxygen, nutrients, pH, toxins or even other
organisms attacking them.
Plants respond to light, touch, hormones etc.
Animals Developmental signals and others.
Cells do not do anything without a cue or signal. Hence all the normal
functions of a cell require signals/cues.
From this view point all the pathological conditions/diseases are due to
deregulation of one or more signaling pathways.
Understanding of signaling pathways is essential so that we can target them
for therapeutic interventions.
Signals, ligands and receptors
Signals in biology refer to the molecules, ions, gases, sound, mechanical
touch, stress, temperature, heat and physical factors that elicit a response
when they communicate/contact with a cell or when they bind or diffuse into a
cell.
If the signal comes from outside the cell extracellular signal.
If the signal is generated inside the cell - intracellular signal.
If the signaling molecule binds with a receptor - call it a Ligand/agonist/first
messenger (with a message).
Receptors bind with ligands and can be located on the cell surface, cytosol or
nucleus.
Ligands/ First messengers
Lipophilic molecules can enter the membrane and bind to intracellular
receptors: steroids, thyroxine, and retinoic acids.
Lipophilic molecules binding to cell surface receptors: prostaglandins.
Hydrophilic molecules that are not able to cross the membrane bind to cell
surface receptors:
peptides: growth hormones, cytokines, gastrin, glucagon, insulin, TSH,
LH, FSH, Parathyroid hormone, secretin
b) amino acid derivatives : epinephrine, norepinephrine, serotonin,
dopamine, histamine.
Some ligands are initially synthesized as trans membrane inactive proteins
and then cleaved by enzymes and secreted out into the extracellular
compartment Growth factors
The word signal transduction started to appear in the biological literature in
the 1970s.
GTP and GTP-binding proteins in metabolic regulation were described
by Alfred G. Gilman and Martin Rodbell
They were awarded the Nobel Prize in 1994 for their discovery of G-
proteins and their role in signal transduction in cells
Signaling Molecules Operate Over Various Distances
Animal and plant cells
Have cell junctions that directly connect the cytoplasm of adjacent cells
Cell junctions: Both animals and plants have cell junctions that allow molecules to
pass readily between adjacent cells without crossing plasma membranes
Plasma membranes
Plasmodesmata
between plant cells
Gap junctions
between animal cells
In local signaling, animal cells
May communicate via direct contact
Specificity
Specificity is an important criterion in ligand-receptor interactions. High
specificity means the ligand binds with a specific receptor that is expressed
only in certain cell types.
Receptor and ligand generally have complementary structural features.
Non-covalent interactions similar to antigen-antibody reactions and enzyme-
substrate reactions with high affinity (low Kd values) co-operativity.
Amplification
The actual cell concentrations of ligands may be very low and are often
transient and short-lived but the effects they ellicit are not small and may be
some major changes.
Ligand-receptor binding may result in the activation of a cascade of enzymes.
Amplification is achieved through multiple enzymes and scaffolding proteins.
Signal integration
Cells often receive multiple signals and they can be conflicting signals from
reciprocal pathways
Parallel signaling pathways may be activated
Several signaling pathways may also work for a common goal
Therefore the signals, pathways and systems have to be coordinated to
provide an integrated cellular response
Termination of signal/Desensitization
A transient signal emanating from a ligand must produce a rapid and major
cellular response.
Sometimes the signal persists and the sensitivity to the ligand decreases.
Desensitization can be ahieved by a feedback loop, dephosphorylation,
endocytosis.
The receptor may now have less affinity, less activity or less expression.
Cell-surface and nuclear receptors
G Protein Coupled receptors
Ion-channel receptors
Receptor tyrosine kinases
Receptor serine/threonine kinases
Receptors with phosphatase activity
Receptors lacking enzyme activity but associate with intracellular enzymes
Cell adhesion receptors
Nuclear receptors
Transduction
Transduction means the action of leading across or bringing across
The action of transferring the signal from one compartment of the cell to
another or to transmit the signal from outside to inside
Conveying the message from the signal/ligand into a response that is
essentially a chemical change
This is mediated by receptors and signaling intermediates
Intracellular signaling is often initiated with second messengers such as cAMP
Earl W. Sutherland was awarded the Nobel Prize in 1971 for his discoveries
concerning the mechanisms of action of hormones.
Identification of cyclic AMP (cAMP) as the second messenger to adrenaline or
glucagon was a great discovery as it became possible to link activation of
specific classes of receptors with specific biochemical responses.
Signaling intermediates
Cellular signaling intermediates include kinases, phosphatases, GTPases and
adapter proteins with interaction domains forming a scaffold.
They help in transmitting the signal and its amplification
Responses
Cells need cues or signals to carry out their functions or physiological
processes.
What are the physiological processes?
Development, proliferation, differentiation, migration, cell death, survival etc
need signals.
Major events of Signal transduction
Generation of signals
Ligands
Recognition of signals
Receptors
Transduction and amplification
Change of external signal into intracellular message
Effects or responses
Modification of cell behavior, gene expression, function etc
Termination/Desensitization of signals
Receptor endocytosis, Dephosphorylation
Dimerization
Homodimers formed between two identical receptors
EGFR-EGFR
Heterodimers formed between two different receptors
EGFR-ErbB2
What are the advantages of dimerization?
Dimerization is an important mechanism for signal transduction
Dimers have certain advantages in signaling than a monomer
Relative distance and orientation of dimers (apart from ligands some
antibodies
can also activate some RTKs by their ability to cross bridge the dimers)
Specificity can be generated for the ligand in a heterodimer
Only one receptor may have the binding site for the ligand
Even if one partner is inactive in its enzyme activity the other one can bind
Increased affinity may be achieved through multiple contact points
Two receptors may bring in several ligands for the given signaling pathway
Multiple intracellular interaction partners
Cross phosphorylation or transphosphorylation is achieved by dimers
Phosphorylation
Phosphorylation is an important mechanism of receptor
activation.
More than 99% of the phosphoamino acids in normal cells
are phosphothronine and phosphoserine.
Phosphotyrosine constitutes only 0.05 0.1 % of total
phosphoamino acids but very important!
R
R
Homodimer
Heterodimer
Ligand binding not
shown for simplicity
P
P
P
P
P
P
P
P
Study Questions
1. What do we mean by signals?
2. Distinguish the differences between homo and heterodimers
3. Lipophilic molecules binding to cell surface receptors a) Tyrosine b)
Androgen c) Prostaglandins d) Estrogen
4. Match the following
RTK Estrogen
Peptide hormone G-proteins
Steroid hormone Insulin
Martin Rodbell EGFR
5. --------------is a well-known second messenger