Biochemistry VIII Tuesday, 23 November 2021

Signal Transduction I

In multicellular animals, cells communicate through small molecules, called signal

molecules.
A cell targeted by a particular signal has a receptor protein that recognizes the signal
molecule
Receptors
For a cell to respond to a signal molecule, it must have a receptor protein. There are two
types of cell receptors:
- Cell-Surface Receptors: integral, transmembrane proteins
- Intracellular Receptors: mainly found in the nucleus of the cell, not embedded to plasma
membrane.
How signals may act on a target cell
Contact-Dependent: is a type of cell–cell or cell–extracellular matrix signalling in
multicellular organisms that requires close contact. Important during development and
immune responses.
Paracrine: In this case, cells live very close. A signal cell produces a signal molecule by
exocytosis, and this molecule interacts with the receptor of the nearby cell.
Autocrine: A single cell is both the target and signal cell. The cell produces signal molecules
and when the molecules are released to the extracellular space, the cell activates its own as
the target cell.
Endocrine: A strategy for signalling over long distances. Cells secrete their signal molecules,
called hormones, into the bloodstream, which carries the molecules far and wide, allowing
them to act on target cells that may lie anywhere in the body. Signals usually get mixed up in
the bloodstream, so speci c and high-af nity receptors are needed.
Synaptic: Transduction seen in neurons (cells of the nervous system). When activated by
stimuli from the environment or from other nerve cells, the neuron sends electrical impulses
rapidly along its axon; when the impulse reaches the synapse, it triggers the secretion of a
neurotransmitter, which is delivered speci cally to receptors on the postsynaptic target cell. A
single neuron can feed different targets with the same signal, producing different responses.
Signal properties
Speci city: A signal molecule ts the binding site on its complementary receptor; other
signals do not t.
Ampli cation: When enzymes activate enzymes, the number of affected molecules increases
geometrically in an enzyme cascade.
Speed: When the response requires only changes in proteins already present in the cell, it can
occur very rapidly. When the response involves changes in gene expression and synthesis of
new proteins, it may require many minutes or hours, regardless of the mode of signal
delivery.
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 Biochemistry VIII Tuesday, 23 November 2021
Integration: Different kinds of signals can arrive to the cell at the same time. If this is the
case, the cells need to decide and choose the signals it will receive.
Different responses and cross talk
When a signal molecule binds to identical receptor proteins, usually different responses
are produced although the receptors are the same, because the types of target cells are
different. The same occurs for cells that have different receptors but a same ligand, because
the cells targeted are different.
Cross talk: To properly perform their functions, cells have to be able to integrate the different
signals and act accordingly. To integrate the signals, signaling pathways usually “cross-talk”,
this implies converging to a common molecule that transmits the integrated signal
downstream.
Enzyme Coupled receptors:
There are receptors whose mechanism is closely related to enzymes. In such cases, the
binding of the ligand triggers some catalytic activity: either the receptor becomes an enzyme
itself, or it associates with one. Afterwards, different signaling complexes associate to
activated receptors. Commonly a docking protein binds to the receptors and provides binding
sites for downstream signalling molecules. In other cases, phosphorylation of the receptors
acts as its own docking complex.
IX. Signal transduction II
MAJOR CLASSES OF MEMBRANE RECEPTORS
RECEPTOR TYROSINE KINASES (RTKs)
RTKs are associated with cell growth and proliferation. They are proteins that are crossing
the plasma membrane. They are composed of two domains:
- Lingand Domain: where the ligand binds.
- Intracellular Domain: enzymatic (catalytic domain).
We have two close receptor proteins that form a dimer when the lingand binds to them.
When they dimerize, the catalytic domain activates, due to a conformational change of the
protein. This catalytic domain is the tyrosine kinase. Its substrate is the other chain/member
that forms the dimer. The two receptor proteins phosphorylate each other.
Once the two receptor chains (dimerized) have become phosphorylated, the process of
transduction starts. Phosphorylation of tyrosine outside the kinase domain creates high
af nity docking sites for the binding of speci c intracellular signalling proteins.
One of the possible routes is the MAPk SIGNALLING PATHWAY:
- A lingand binds to the extraceullar portion of the membrane bound receptor (tyrosine
kinases).
- The subunits of the receptor dimerize and at the inner side the tyrosine kinase domains
catalyze the phosphorylation of the other subunit.
- GRB 2 protein binds to the phosphorylated RTK, Protein SOS binds to GRB 2 protein,
inactive Ras-GDP binds to SOS protein. GDP is exchanged for GTP by SOS protein.
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Biochemistry VIII Tuesday, 23 November 2021
- Ras protein is activated and binds to effector proteins such as B-Raf, which phosphorylates
and activates the kinases MEK 1 and 2 and ERK 1 and 2.
- The kinase cascade activates transcription factors of the AP-1 protein, such as jun and fos.
When activated they move to the cell nucleus, where they form an heterodimer and bind to
an AP1 motif of the DNA. These leads to the expression of genes and coding of growth
factors. Cell proliferation is activated.
- In a normal cell, Ras-GTP complex is inactivated so that an active MAPK pathway (cell
proliferation would not be stopped, leading to cancer) and its undesirable effects are
avoided. Deactivation is made by GAP protein.
Another possibility is the PI3K-AKT SIGNALLING PATHWAY:
- PI3K is activated, when it binds to the phosphorylated RTK. It can also be activated when
it binds to IRS-1 (insulin receptor), who was previously attached to RTK.
- Activated PIK3 binds to PIP2 and phosphorylates it into PIP3
- PIP3 Activates AKT protein. AKT inhibits apoptosis, activates protein translation and
lowers the concentration of some proteins in the organism such as FOXO and inactivates
glycogen synthase kinase.
Cross-activation cases
In some cases, IRS-1 is phosphorylated and instead of binding to PIK3, it binds to MAPk
pathway through GBR-2.
CYTOKINE RECEPTORS
They don’t have enzymatic activity themselves but have molecules tightly associated
which have a tyrosine kinase activity, called JAKs.
THE JAK-STATs PATHWAY
- The binding sites binds the lingand (cytokine). The receptor is dimerized. JAKs are
phosphorylated, bind to the receptor, and phosphorylate the cytokine receptor
- STAT proteins bind to the phosphorylated tyrosine residues of the receptors. STATS are
phosphorylated and dissociate from the receptor and dimerize. Phosphorylated STATS
enter the nucleus, where they bind to speci c promoter motifs of DNA known as CREs
(cytokine responsive elements). STATS activate the transcription of many genes.
G-PROTEIN COUPLED RECEPTORS
The G-protein is composed of three important subunits:
Alpha: has the ability to bind to GDP
Beta: linked to the plasma membrane
Gamma: formed by non covalent bonds
In the absence of a signal, the G protein has a GDP binded to its alpha subunit. When a
lingand binds to the receptor, the G protein changes its conformation and replaces its GDP for
GTP. The activated alpha subunit, separates from the other two subunits. The activated alpha
subunit regulates the activity of target proteins in the plasma membrane. The activated target
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Biochemistry VIII Tuesday, 23 November 2021
proteins relay the signal to other components in a signalling cascade. For example, alpha
subunit activates cyclase, which converts ATP into cAMP (second messenger). cAMP will
activate other molecules. G-protein inactivates the subunit by hydrolyzing its bound GTP to
GDP. The 3 subunits bind to each other again and the process is repeated.
The Beta and Gamma subunits, when activated, often target Ion Channels.
TGFBeta RECEPTORS
Dimeric proteins, they mainly control organ size.
There are two classes: I and II. The binding of the signal brings the kinase domains
together so the type II receptor phosphorylates and activates the type I receptor.
The type I receptor binds to a latent gene regulatory protein of the Smad family (1,2,3,5,8)
and phosphorylates it. Once one of these receptor activated smads is phosphorylated, it
dissociate from the receptor and binds to Smad 4, which can form an heterodimer. The Smad
complex translocates into the nucleus, where it associates with other gene regulatory proteins
and regulates the transcription of speci c target genes.
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