Cell biology and immunology
Lecture 1: cell signaling and cell-cell communication
Cell signaling
Cell signaling encompasses:
- Cell-cell communication
- Sensing and interacting with the extracellular environment
- Sensing and responding to changes in the intracellular environment
4 modes of inter-cellular signaling
Contact dependent
- Short distance
- Direct cell-to-cell contact
- Important in embryonic development and immune
responses
Paracrine
- Short distance (without contact)
- Secreted signal molecules, close by cells detect the molecule and act on it.
- Modulate response in nearby cells
- Important in inflammation response
Synaptic
- Long distance
- Fast (action potential travels with 100m/sec)
- Neurotransmitters
- Regulated exocytosis into the synaptic cleft
Endocrine
- Long range, broad
- Signal molecules: hormones
- Secretion into the bloodstream
- E.g., insulin, adrenaline
Extracellular signal molecule
- Chemicals (e.g., nutrieints, hormones, odors, DNA/RNA)
- Physical cues (e.g., pressure, temperature, light)
This all can be detected and translated into a biochemical signal. Regardless of the nature of the
signal, the target cell responds by means of a receptor, which binds the signal molecule and then
initiates a response in the target cell. The binding site of the receptor has a complex structure that is
shaped to recognize the signal molecule with high specificity, helping to ensure that the receptor
responds only to the appropriate signal and not to the many other signaling molecules the cell is
exposed to.
,Receptor protein
Cell surface receptors → large, hydrophilic signal molecules, can’t cross the
membrane
- Ion-channel coupled receptors
- G-protein coupled receptors (GPCRs)
- Enzyme-coupled receptors (e.g., receptor tyrosine kinases
Intracellular receptors → small, hydrophobic molecules (e.g., steroids, gases),
will be able to interact with the lipid and cross the membrane
- Nuclear receptors (directly activating transcription factors)
Combination of inputs create different responses
Each cell type displays a set of receptors that enables it to respond to a
corresponding set of signal molecules produced by other cells. These signal
molecules work in various combinations to regulate the behavior of the cell.
As shown here, an individual cell often requires multiple signals to survive
(blue arrows) and additional signals to grow and divide (red arrows) or
differentiate (green arrows). If deprived of appropriate survival signals, a cell
will undergo a form of cell suicide known as apoptosis. The actual situation is even more complex.
Although not shown, some extracellular signal molecules act to inhibit these and other cell behaviors
or even to induce apoptosis.
The same input can create distinct responses in different cell
types. It’s really dependent on which cell and which receptor the
signaling molecule binds.
Signaling networks are often highly complex
Breaking down large networks into small modules helps us to understand
these networks better.
Signaling motifs
Easy examples: A activates or inhibits B.
Some signaling motifs occur over and over
again in cellular signaling. Positive
feedback: C activates B. Negative
feedback: C inhibits B. incoherent
feedforward loop: 1 inhibits and 1 activates C. Coherent feedforward loop: together they activate C.
Regulation of signaling proteins (molecular switches)
Cellular signaling is a mix and match between these different
mechanisms.
,Ligand-binding receptors
Ion-channel coupled receptors
Ligands:
- Neurotransmitters: acetylcholine, glycine, glutamate, GABA
- Second messengers: inositol-1,4,5-triphosphate, Ca2+
Structure:
- Heterogenous family of multipass transmembrane proteins
- Often with several subunit
Mode of action:
- Ligand-binding induces opening or closing of the
channel to regulate ion influx/outflux
G-protein-coupled receptors (GPCRs)
A large class of receptors that bind almost everything. They are very stereotypic in structure.
Ligands:
- Neurotransmitters
- Proteins
- Peptides
- Hormones
- Derivatives of aa’s and FAs
Structure
- Single polypeptide chain
- 7 transmembrane helices
Mode of action:
- Ligand-binding induces conformational change in
the intracellular domain
- Associate and regulate the activity of intracellular
heterotrimeric G proteins
Angiotensin II type 1 – AT1 receptor (mediates
constriction of blood vessels). You see the bound and
unbound state. It binds on the bottom.
Enzyme-coupled receptors
- Receptor tyrosine kinases (RTKs) → an enzyme itself
- Cytokine receptors → not an enzyme itself
Ligands
, - Mainly signal protein ligands (e.g. insulin, growth factors,
cytokines)
Structure:
- Typically single pass membrane domain
- Directly encode or are tightly associated with an intracellular kinase
Mode of action
- Ligand-binding induces dimerization
- Dimerization leads to inter- and intramolecular phosphorylation of the receptor
- Phosphorylated receptors act as scaffold to recruit additional proteins
Receptor tyrosine kinases (RTKs)
They are very variable on the outside but
stereotypically on the inside. The binding of the
signal protein to the ligand binding domain on the
extracellular side of the receptor activates the
tyrosine kinase domain on the cytosolic side. This
leads to phosphorylation of tyrosine side chains on
the cytosolic part of the receptor, creating
phosphotyrosine docking sites for various
intracellular signaling proteins that relay the signal.
Binding of ligand brings two monomers together to
form a dimer. The close proximity in the dimer leads
the two kinase domains to phosphorylate each other,
which has two effects. First, phosphorylation at some
tyrosines in the kinase domains promotes the
complete activation of the domains. Second, phosphorylation at tyrosines in other parts of the
receptors generates docking sites for intracellular signaling proteins, resulting in the formation of
large signaling complexes that can then broadcast signals along multiple signaling pathways.
Cytokine receptor
The large family of cytokine receptors includes
receptors for many kinds of local mediators
(collectively called cytokines), as well as receptors for
some hormones. These receptors are stably
associated with cytoplasmic tyrosine kinases called
Janus kinases (JAKs), which phosphorylate and activate transcription regulators called STATs (signal
transducers and activators of transcription). STAT proteins are located in the cytosol and are referred
to as latent transcription regulators because they migrate into the nucleus and regulate gene
transcription only after they are activated.
Cytokine binding alters the arrangement so as to bring two JAKs into close proximity so that they
phosphorylate each other, thereby increasing the activity of their tyrosine kinase domains. The JAKs
then phosphorylate tyrosines on the cytoplasmic tails of cytokine receptors, creating
phosphotyrosine docking sites for STATs
Lecture 1: cell signaling and cell-cell communication
Cell signaling
Cell signaling encompasses:
- Cell-cell communication
- Sensing and interacting with the extracellular environment
- Sensing and responding to changes in the intracellular environment
4 modes of inter-cellular signaling
Contact dependent
- Short distance
- Direct cell-to-cell contact
- Important in embryonic development and immune
responses
Paracrine
- Short distance (without contact)
- Secreted signal molecules, close by cells detect the molecule and act on it.
- Modulate response in nearby cells
- Important in inflammation response
Synaptic
- Long distance
- Fast (action potential travels with 100m/sec)
- Neurotransmitters
- Regulated exocytosis into the synaptic cleft
Endocrine
- Long range, broad
- Signal molecules: hormones
- Secretion into the bloodstream
- E.g., insulin, adrenaline
Extracellular signal molecule
- Chemicals (e.g., nutrieints, hormones, odors, DNA/RNA)
- Physical cues (e.g., pressure, temperature, light)
This all can be detected and translated into a biochemical signal. Regardless of the nature of the
signal, the target cell responds by means of a receptor, which binds the signal molecule and then
initiates a response in the target cell. The binding site of the receptor has a complex structure that is
shaped to recognize the signal molecule with high specificity, helping to ensure that the receptor
responds only to the appropriate signal and not to the many other signaling molecules the cell is
exposed to.
,Receptor protein
Cell surface receptors → large, hydrophilic signal molecules, can’t cross the
membrane
- Ion-channel coupled receptors
- G-protein coupled receptors (GPCRs)
- Enzyme-coupled receptors (e.g., receptor tyrosine kinases
Intracellular receptors → small, hydrophobic molecules (e.g., steroids, gases),
will be able to interact with the lipid and cross the membrane
- Nuclear receptors (directly activating transcription factors)
Combination of inputs create different responses
Each cell type displays a set of receptors that enables it to respond to a
corresponding set of signal molecules produced by other cells. These signal
molecules work in various combinations to regulate the behavior of the cell.
As shown here, an individual cell often requires multiple signals to survive
(blue arrows) and additional signals to grow and divide (red arrows) or
differentiate (green arrows). If deprived of appropriate survival signals, a cell
will undergo a form of cell suicide known as apoptosis. The actual situation is even more complex.
Although not shown, some extracellular signal molecules act to inhibit these and other cell behaviors
or even to induce apoptosis.
The same input can create distinct responses in different cell
types. It’s really dependent on which cell and which receptor the
signaling molecule binds.
Signaling networks are often highly complex
Breaking down large networks into small modules helps us to understand
these networks better.
Signaling motifs
Easy examples: A activates or inhibits B.
Some signaling motifs occur over and over
again in cellular signaling. Positive
feedback: C activates B. Negative
feedback: C inhibits B. incoherent
feedforward loop: 1 inhibits and 1 activates C. Coherent feedforward loop: together they activate C.
Regulation of signaling proteins (molecular switches)
Cellular signaling is a mix and match between these different
mechanisms.
,Ligand-binding receptors
Ion-channel coupled receptors
Ligands:
- Neurotransmitters: acetylcholine, glycine, glutamate, GABA
- Second messengers: inositol-1,4,5-triphosphate, Ca2+
Structure:
- Heterogenous family of multipass transmembrane proteins
- Often with several subunit
Mode of action:
- Ligand-binding induces opening or closing of the
channel to regulate ion influx/outflux
G-protein-coupled receptors (GPCRs)
A large class of receptors that bind almost everything. They are very stereotypic in structure.
Ligands:
- Neurotransmitters
- Proteins
- Peptides
- Hormones
- Derivatives of aa’s and FAs
Structure
- Single polypeptide chain
- 7 transmembrane helices
Mode of action:
- Ligand-binding induces conformational change in
the intracellular domain
- Associate and regulate the activity of intracellular
heterotrimeric G proteins
Angiotensin II type 1 – AT1 receptor (mediates
constriction of blood vessels). You see the bound and
unbound state. It binds on the bottom.
Enzyme-coupled receptors
- Receptor tyrosine kinases (RTKs) → an enzyme itself
- Cytokine receptors → not an enzyme itself
Ligands
, - Mainly signal protein ligands (e.g. insulin, growth factors,
cytokines)
Structure:
- Typically single pass membrane domain
- Directly encode or are tightly associated with an intracellular kinase
Mode of action
- Ligand-binding induces dimerization
- Dimerization leads to inter- and intramolecular phosphorylation of the receptor
- Phosphorylated receptors act as scaffold to recruit additional proteins
Receptor tyrosine kinases (RTKs)
They are very variable on the outside but
stereotypically on the inside. The binding of the
signal protein to the ligand binding domain on the
extracellular side of the receptor activates the
tyrosine kinase domain on the cytosolic side. This
leads to phosphorylation of tyrosine side chains on
the cytosolic part of the receptor, creating
phosphotyrosine docking sites for various
intracellular signaling proteins that relay the signal.
Binding of ligand brings two monomers together to
form a dimer. The close proximity in the dimer leads
the two kinase domains to phosphorylate each other,
which has two effects. First, phosphorylation at some
tyrosines in the kinase domains promotes the
complete activation of the domains. Second, phosphorylation at tyrosines in other parts of the
receptors generates docking sites for intracellular signaling proteins, resulting in the formation of
large signaling complexes that can then broadcast signals along multiple signaling pathways.
Cytokine receptor
The large family of cytokine receptors includes
receptors for many kinds of local mediators
(collectively called cytokines), as well as receptors for
some hormones. These receptors are stably
associated with cytoplasmic tyrosine kinases called
Janus kinases (JAKs), which phosphorylate and activate transcription regulators called STATs (signal
transducers and activators of transcription). STAT proteins are located in the cytosol and are referred
to as latent transcription regulators because they migrate into the nucleus and regulate gene
transcription only after they are activated.
Cytokine binding alters the arrangement so as to bring two JAKs into close proximity so that they
phosphorylate each other, thereby increasing the activity of their tyrosine kinase domains. The JAKs
then phosphorylate tyrosines on the cytoplasmic tails of cytokine receptors, creating
phosphotyrosine docking sites for STATs
