2022-2023 Laura van den End
1. Introduction
All cells must have the ability to detect the presence Electrical and synaptic
of extracellular molecules and conditions + to Fast and efficient: via changes in electrical potential
instigate a range of intracellular responses. across the PM of a cell (neuron) → propagated along
the length of the cell =
The main principles of cell signaling travel over a distance.
Arrival at the cell of something that requires the cell
to respond = main underlying event for signal
From here, the signal is
mechanisms.
passed on to the next
- e.g: light photons in the eyes; chemicals released to
neuron or target tissue
another organism or to another cell.
- Most signals arrive at, and perceived at, the outer
borders of the cell (PM)
For conduction of the
Followed by the arrival of the signal signal
1. Perception: usually by receptors.
2. Transmission: by the receptor into the cell or next
signaling component (intracellular).
Contains the nucleus and
3. Passing on the message to a series of cell
normal cellular functions
signaling components (cascade).
4. Arrival of the message at final destination (e.g
Receive chemical signals
nucleus or cytoplasm).
from other neurons to
5. Response by the cell
other cells
A signal may lead to more than one outcome, a Areas of close contact through
signal can lead to the activation and use of moe which a signal can be propagated.
signaling cascades.
A small amount of the signal might be perceived for Transmitting electrical signal directly through gap
a large response. junctions or release of neurotransmitters
Crosstalk may occur: one signaling pathway is
influenced by another → cells do not respond to all Chemical
the signals present.
A signal is always amplified Release of signal mol
(hormones), which can
What makes a good signal? travel via blood to target
1. Specificity: to relay a defined signal and to be cells at a distance.
detected only by the right receptor.
2. Relatively small: travel easily to target site The released mol are
3. Made, mobilized or altered quickly detected and have their
- Enzyme can be employed to make the signal effect in the local area of
when required the signaling cell.
- Pre-made signal can be sequestered, and The released mol act on
released only at the right time the the same cell that
released them. Common
Di erent ways in cell to cell signaling with Growth Hormones.
Depending on the distance between the signaling cell
The signal is transferred
and the target cell.
via membrane bound
- If cells are touching → pores in membranes or via
ligands that are detected
ligand detected by receptor.
by adjacent receptors.
- If cells are further away: release of molecules or
transmission of electrical signal. Steroid hormones: can transverse a membrane (they
are made of cholesterol = part of the membrane
itself).
Mechanisms of signal transduction
ff
, 2022-2023 Laura van den End
Receptors, channels and pumps Protein sorting
When a protein is translated by the ribosomes, they
need to be sorted and transferred to the right
organelle (have their own proteins and functions).
mRNA with ribosomes
ER signal sequence nothing target sequence
RER Cytosolic Mitochondrion
protein Chloroplast
Golgi complex Peroxisome
Nucleus
PM
lysozome
Interorganelle communication
All organelles are connected to each other by
membrane contact sites = formed by special tetanine
proteins.
- Tightly controlled by the metabolism - not
permanently formed ~ dynamic
- Important to exchange lipids
- Aa transporters between vacuole and lysosomes
→ broken down in aa = recycling
Propagation mechanisms Each cell is a different environment
pH is very important - optimum for an enzyme.
Exo/endocytosis, ecto/endosomes Certain enzymes can only work at a particular pH.
Ectosomes are formed from multi vesicular bodies
Endosomes are formed from PM. PROTEIN DEGRADATION
1 ubiquitin on different aa residues OR multiple
ubiquitin on one aa → completely different trajectory
of degradation
PROTEIN TRANSLOCATION
- TF are captured in cytoplasm till activated
- Kinases move
- Bax: protein in apoptosis ~ migrating into the
mitochondria. Takes about 2 hours to stain the
mitochondrial membrane with GFP bax.
Gap junctions - Cellular signaling circuits are temporally and
Found in epithelial cells spatially controlled. They are composed from a
Usually for ions and small chemicals modular toolkit of components, including kinases,
phosphatases, GTPases, and regulated by protein
post-translational modifications and protein
interactions.
- Think in modules
- Molecular switches
regulated by phosphory-
lation (conformational
changes).
Mechanisms of signal transduction
, 2022-2023 Laura van den End
PROTEIN (IN)ACTIVATION Second messengers amplify signals
- GTP loading is regulated by GEF (like Sos) → - PIP2 → DAG and IP3 (catalyzed by phospholipase
facilities the exchange of GDP into GTP. Once GTP C, PLC) → can react via IP3 gated Ca2+ channels →
loaded: GAP reconverts GTP into GDP/ Ca2+ binds PKC → with the help of DAG
- 2 types: small (with a single subunit, like Ras) or substrates can be phosphorylated.
heterotrimeric: α can bind GTP → release β and γ - ATP → cAMP (catalyzed by adenylate cyclase) →
activates PKA which can enter the nucleus and
PROTEIN- PROTEIN INTERACTIONS play a role in the transcription of CRE.
Can be studied with:
- Classical yeast-2-Hybrid Feedback control and crosstalk
- Reporter: transcription
- SOS recruitment
- Reporter: signaling
- Ras recruitment
- Reporter: signaling
- Split ubiquitin
- Reporter: transcription
PROTEIN LIPID ANCHORS
To keep proteins in the proper place, some proteins Feedfoward: prepare proteins for secondary
are embedded in the membrane, others are not. pathway. E.g. expose epitopes
Pleckstrin homology (PH) domains target proteins to
membranes; Akt’s PH domain binds PI3Kinase Junk
- Play a role in the activation of Akt/PKB: Only 2% of the genome is coding, the rest is not junk.
phosphorylation of Ptdins → the PH domain can They could be small peptides or non-coding RNAs
now bind = change in subcellular localization and
PDK1 and mTOR can now phosphorylate the
Kinase and regulatory domain of PKB, thereby
releasing it from the membrane and activating it.
- 14-3-3 proteins play a role in the regulation and
control of the Act.PKB protein: bind phospho-
proteins (pSer/pThr), and holds them inactive or
protects he phosphorylations.
Signal ampli cation
Mechanisms of signal transduction
fi
1. Introduction
All cells must have the ability to detect the presence Electrical and synaptic
of extracellular molecules and conditions + to Fast and efficient: via changes in electrical potential
instigate a range of intracellular responses. across the PM of a cell (neuron) → propagated along
the length of the cell =
The main principles of cell signaling travel over a distance.
Arrival at the cell of something that requires the cell
to respond = main underlying event for signal
From here, the signal is
mechanisms.
passed on to the next
- e.g: light photons in the eyes; chemicals released to
neuron or target tissue
another organism or to another cell.
- Most signals arrive at, and perceived at, the outer
borders of the cell (PM)
For conduction of the
Followed by the arrival of the signal signal
1. Perception: usually by receptors.
2. Transmission: by the receptor into the cell or next
signaling component (intracellular).
Contains the nucleus and
3. Passing on the message to a series of cell
normal cellular functions
signaling components (cascade).
4. Arrival of the message at final destination (e.g
Receive chemical signals
nucleus or cytoplasm).
from other neurons to
5. Response by the cell
other cells
A signal may lead to more than one outcome, a Areas of close contact through
signal can lead to the activation and use of moe which a signal can be propagated.
signaling cascades.
A small amount of the signal might be perceived for Transmitting electrical signal directly through gap
a large response. junctions or release of neurotransmitters
Crosstalk may occur: one signaling pathway is
influenced by another → cells do not respond to all Chemical
the signals present.
A signal is always amplified Release of signal mol
(hormones), which can
What makes a good signal? travel via blood to target
1. Specificity: to relay a defined signal and to be cells at a distance.
detected only by the right receptor.
2. Relatively small: travel easily to target site The released mol are
3. Made, mobilized or altered quickly detected and have their
- Enzyme can be employed to make the signal effect in the local area of
when required the signaling cell.
- Pre-made signal can be sequestered, and The released mol act on
released only at the right time the the same cell that
released them. Common
Di erent ways in cell to cell signaling with Growth Hormones.
Depending on the distance between the signaling cell
The signal is transferred
and the target cell.
via membrane bound
- If cells are touching → pores in membranes or via
ligands that are detected
ligand detected by receptor.
by adjacent receptors.
- If cells are further away: release of molecules or
transmission of electrical signal. Steroid hormones: can transverse a membrane (they
are made of cholesterol = part of the membrane
itself).
Mechanisms of signal transduction
ff
, 2022-2023 Laura van den End
Receptors, channels and pumps Protein sorting
When a protein is translated by the ribosomes, they
need to be sorted and transferred to the right
organelle (have their own proteins and functions).
mRNA with ribosomes
ER signal sequence nothing target sequence
RER Cytosolic Mitochondrion
protein Chloroplast
Golgi complex Peroxisome
Nucleus
PM
lysozome
Interorganelle communication
All organelles are connected to each other by
membrane contact sites = formed by special tetanine
proteins.
- Tightly controlled by the metabolism - not
permanently formed ~ dynamic
- Important to exchange lipids
- Aa transporters between vacuole and lysosomes
→ broken down in aa = recycling
Propagation mechanisms Each cell is a different environment
pH is very important - optimum for an enzyme.
Exo/endocytosis, ecto/endosomes Certain enzymes can only work at a particular pH.
Ectosomes are formed from multi vesicular bodies
Endosomes are formed from PM. PROTEIN DEGRADATION
1 ubiquitin on different aa residues OR multiple
ubiquitin on one aa → completely different trajectory
of degradation
PROTEIN TRANSLOCATION
- TF are captured in cytoplasm till activated
- Kinases move
- Bax: protein in apoptosis ~ migrating into the
mitochondria. Takes about 2 hours to stain the
mitochondrial membrane with GFP bax.
Gap junctions - Cellular signaling circuits are temporally and
Found in epithelial cells spatially controlled. They are composed from a
Usually for ions and small chemicals modular toolkit of components, including kinases,
phosphatases, GTPases, and regulated by protein
post-translational modifications and protein
interactions.
- Think in modules
- Molecular switches
regulated by phosphory-
lation (conformational
changes).
Mechanisms of signal transduction
, 2022-2023 Laura van den End
PROTEIN (IN)ACTIVATION Second messengers amplify signals
- GTP loading is regulated by GEF (like Sos) → - PIP2 → DAG and IP3 (catalyzed by phospholipase
facilities the exchange of GDP into GTP. Once GTP C, PLC) → can react via IP3 gated Ca2+ channels →
loaded: GAP reconverts GTP into GDP/ Ca2+ binds PKC → with the help of DAG
- 2 types: small (with a single subunit, like Ras) or substrates can be phosphorylated.
heterotrimeric: α can bind GTP → release β and γ - ATP → cAMP (catalyzed by adenylate cyclase) →
activates PKA which can enter the nucleus and
PROTEIN- PROTEIN INTERACTIONS play a role in the transcription of CRE.
Can be studied with:
- Classical yeast-2-Hybrid Feedback control and crosstalk
- Reporter: transcription
- SOS recruitment
- Reporter: signaling
- Ras recruitment
- Reporter: signaling
- Split ubiquitin
- Reporter: transcription
PROTEIN LIPID ANCHORS
To keep proteins in the proper place, some proteins Feedfoward: prepare proteins for secondary
are embedded in the membrane, others are not. pathway. E.g. expose epitopes
Pleckstrin homology (PH) domains target proteins to
membranes; Akt’s PH domain binds PI3Kinase Junk
- Play a role in the activation of Akt/PKB: Only 2% of the genome is coding, the rest is not junk.
phosphorylation of Ptdins → the PH domain can They could be small peptides or non-coding RNAs
now bind = change in subcellular localization and
PDK1 and mTOR can now phosphorylate the
Kinase and regulatory domain of PKB, thereby
releasing it from the membrane and activating it.
- 14-3-3 proteins play a role in the regulation and
control of the Act.PKB protein: bind phospho-
proteins (pSer/pThr), and holds them inactive or
protects he phosphorylations.
Signal ampli cation
Mechanisms of signal transduction
fi
