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321 Immune Receptors and Signal Transduction

Friday, Oct 13, 2023

Chapter 7
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321 Learning Objectives
• Understand the basic principles of signal transduction

• Understand the basic steps of JAK/STAT signaling

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321 Signaling Basics

• A cellular signal is any event that instructs a cell to change its

metabolic or proliferative state
• Signals are usually generated by the binding of a ligand to a
complementary cell-bound receptor
• A cell can become more or less susceptible to actions of a
ligand by increasing or decreasing expression of the receptor
for that ligand
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321 Signaling Basics

• The ligand may be a soluble molecule or a peptide,

carbohydrate, or lipid presented on the cell surface
• The ligand may travel long distances from its entry point in
either the bloodstream or lymphatics before it reaches a cell
bearing the relevant receptor or it might be produced by a
neighboring cell
• Ligand-receptor binding is noncovalent, although it may be
of quite high affinity
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321 Receptor-ligand interactions
• Receptor-ligand binding occurs
via multiple noncovalent
bonds
• Each individual bond may be
weak
• Many such bonds occur
between receptors and ligands,
providing great cumulative
bond strength
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321 Signaling Basics

• Ligand-receptor binding induces molecular change in the receptor

• Conformational
• Dimerization/clustering
• Location in the membrane
• Covalent modification
• Receptor alterations induce cascades of intracellular events
• Activation of enzymes
• Changes in intracellular locations of molecules
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321 Signaling Basics

• Cell-signaling end results often induce a change in the

transcriptional program of the target cell
• Sometimes multiple signals through multiple receptors are
required to effect particular outcomes
• Integration of all signals received by a cell occurs at the
molecular level inside the recipient cell
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321 Receptor Signaling
• Signal transduction = the intracellular biochemical pathways that are
activated in cells after the binding of ligands to specific receptors
• Cell surface receptors promote
• Cell/gene activation
• Adhesion of one cell to another or to
the extracellular matrix
• Internalization of extracellular
molecules and cells

• Receptors are typically in the

plasma membrane (not always)
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321 Receptor Signaling
1. Ligand binds to receptor
2. A cascade of biochemical
changes in the cytoplasm
Eg. Phosphorylation of proteins
3. Activation and translocation of
nuclear factors into the
nucleus
4. Upregulation or
downregulation of gene
expression
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321 Receptor-ligand interactions
• Antigen-immune system receptor
interactions are enhanced by co-
receptor binding
• These are separate receptor-ligand MHC I MHC II
interactions that may take place near the
original interaction APC
• Often times, a single type of interaction
may be insufficient to lead to an MHC I
activation event Peptide MHC II
• A co-receptor interaction may provide a TCR
Peptid
second signaling interaction to further
signal the cell to proceed with activation TCR
CD8
Eg. CD4 binding MHC II stabilizes
CD4
TCR-MHCII interaction
T-cell
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321 Receptor-ligand interactions
• Receptor-antigen interactions are
usually multivalent
• Multivalency increases avidity of the
interactions
• Individual interactions have an
affinity―a strength of that individual
pairing
• Avidity is the combined strength of
multiple interactions
• An interaction may have weak affinity,
but high overall avidity
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321 Receptor-ligand interactions

• Receptor and ligand expression can

vary during the course of an
immune response
• Eg: white blood cells (blue) treated
with an activating mitogen show
upregulation of the receptor for
cytokine IL-2 (yellow-orange) +mitogen
48H
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321 Receptor-ligand interactions

• Local concentrations of cytokines and

other ligands may be extremely high T-cell
• A cell may direct its secretion machinery
toward a recipient for maximum effect DC
• Eg: blue dendritic cells secreting cytokine IL-
12 (pink) to T cells (green); note the
localization of the cytokine-filled, vesicle-rich
area in the dendritic cell
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321 Receptor-ligand interactions

Categories of signaling receptors

1. Non-receptor tyrosine kinase T-cell

2. Tyrosine kinase receptors

DC
3. Nuclear receptors
4. G protein–coupled receptors
5. Notch family receptors
6. Others…
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321 Receptor Signaling
• Binding of antigen to receptor induces:
• An internal signaling cascade, which leads to
cellular alterations in:
• Motility
• Adhesive properties
• Transcriptional programming

• These cascades are behind the various

cellular changes that take place during an
immune responses
• Often, the same players/proteins are
used in different cell types―triggering
receptors may be different
• Eg. TCR, BCR or FcγRIIA utilize RAS-MAP
kinase, NF-kB, PI3K pathways
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321 Receptor Signaling
• Phosphorylation of serine/threonine
residues is also a common step in
signaling pathways with different
possible outcomes
• May activate an enzyme
• Induce interaction with other proteins
• Alter cellular location
• Protect protein from destruction
• Target the protein for destruction
• Phosphatase = dephosphorylates
• Kinase = phosphorylates
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321 Receptor Signaling
• Signaling molecules are often composed of
distinct modules, each with a specific binding or
catalytic function
• SH2
• SH3
• PH
• Kinase
• Proline-rich region
• Domains interact with each other modulating
location and activity of signaling proteins
• Introns separate domain coding regions
• During evolution domains can be shuffled to
create new proteins
• Adapter proteins help to gather members of
signaling pathways
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321 Receptor Signaling
• LCK is phosphorylated by Csk on Y505
• phosphorylated Y505 binds to SH2 domain
• Inactivates the kinase
• CD45 dephosphorylates Y505
• Releases the from SH2 domain
• Kinase becomes active

• The balance between the activities

of Csk and CD45 dictates the activity
of LCK
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321 Receptor Signaling
• Adapter proteins help to gather members of
signaling pathways
• Adaptors can bind multiple proteins and bringing
them together to facilitate the the propagation
of the signal
• LAT is a transmembrane adaptor protein
• GADS is a cellular adaptor protein
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321 Receptor Signaling
JAK-STAT signaling of cytokine receptors
• Janus kinases (JAKs)
• Signal transducers and activators of transcription (STATs)
1. Inactive JAK enzymes are noncovalently attached to
the cytoplasmic domains of cytokine receptors
2. Binding of a cytokine to the receptor activates JAKs
3. JAKs phosphorylate tyrosine on receptor
4. SH2 domains of cytosolic STATs bind to the
phosphorylated tyrosine
5. STAT proteins are brought close to JAKs and are
phosphorylated
6. STAT monomer binds to a phosphortyrosine residue
on an adjacent STAT forming a dimer
7. STAT dimers migrate to the nucleus
8. STAT dimers bind to specific DNA sequences in the
promoter regions of cytokine-responsive genes and
activate gene transcription
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321 Receptor Signaling
… But it’s much more complicated
• Multiple JAKs
• Multiple STATs
• STATs can form homo-
and hetro-dimers
• The various STAT dimes
bind different
sequences
• Expression pattern of
JAKs and STATS changes
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321 Summary
• Ligand-receptor binding induces molecular change in the receptor
• Receptor alterations induce cascades of intracellular events
• Cell responds to signals
• Change in the transcriptional program
• Metabolism
• Motility/orientation
• Degranulation
• Integration of all signals received by a cell occurs at the molecular
level inside the recipient cell
• Know the basics of JAK/STAT signaling
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321 Summary