3.
Enzyme-coupled receptors:
• Transmembrane proteins
• Ligand-binding domains on outer surface of plasma membrane
• Cytoplasmic domain either acts as an enzyme or forms complex w.
enzyme
Cytoplasmic domains of
transmembrane
Enzyme-coupled receptors proteins either act as
enzymes…..
T
omplex with another protein that acts as enzyme
… or form a complex with
another protein that acts as
enzyme
Characteristics of enzyme-linked pathways
• Regulate growth, proliferation, differentiation & survival of animal
cells
• Also rapid reconfiguration of cytoskeleton
• Largest class have cytoplasmic domain that phosphorylates tyrosine
when active
• Receptor tyrosine kinases (RTKs)
Enzyme coupled receptors – Receptor tyrosine kinase (RTK) pathway:
Activation stimulates the assembly of an
intracellular signaling complex
Example: the insulin
receptor
• Receptor tyrosine
kinase
• Binding of insulin
dimerization
autophosphorylation
activates receptor
phosphorylates
intracellular proteins,
including IRS-1
(insulin-receptor
substrate 1)
http://vcell.ndsu.edu/animations/insulinsignaling/movie-flash.htm
Terminating the signal
Need to end 1st message (binding to receptor, and presence of any
effectors)
1. protein tyrosine phosphatases remove phosphates
2. activated receptors are taken into cells by phagocytosis
• May be digested in lysosomes
• May be recycled back to cell surface
Movie 16.6
Most RTKs activate the monomeric GTPase Ras:
• Ras resembles α-subunit of G proteins – acts as a molecular switch
• Active when bound to GTP – inactive when bound to GDP
This is a protein
Protein kinases can kinase kinase kinase
create phosphorylation
cascades This is a protein
kinase kinase
This is a protein kinase
Ras activates MAP kinase
pathway:
May change gene expression
• stimulate proliferation
• promote cell survival
• induce differentiation
MAP pathways control cell proliferation, promote cell survival or
induce cell differentiation
• Mutation in Ras that
causes hyperactive form
that stimulates cells to
divide even when signals
absent
• Uncontrolled cell
proliferation –> cancer
• About 30% of human
cancers have activating
mutations in Ras
• others have mutations in
Ras pathway
Ex. RTKs activate the PI-3-kinase Akt signaling pathway
Activated Akt promotes cell survival
Akt stimulates cell
growth by activating a
serine/threonine
kinase called Tor
TOR = Target Of Rapamycin
Main GPCR &
RTK pathways
Additional signaling pathways:
Some enzyme linked receptors activate a fast track to
the nucleus
• Don’t involve RTK and complex signaling pathway
• Eg. cytokines in immune system (eg. interferon)
activate gene regulatory proteins that are held at
plasma membrane in inactive form
• Activation moves them directly to nucleus
Interferon uses
this pathway
Direct control of Gene expression:
Notch receptor is a transcription
regulator
Cell – cell communication in
plants:
Ex. Ethylene: Signals act to
relieve transcriptional inhibition
• Kinase is “on” when receptor not
bound – transcription inhibited
• Kinase turned “off” when ethylene
binds – Transcription
With such a simple pathway to the
nucleus, why do most receptors use
very complex pathways?
With such a simple pathway to the nucleus, why
do most receptors use very complex pathways?
Complex pathways are more commonly used.
With more steps, cells have more opportunities to:
• Regulate pathway
• Amplify signal
• Integrate signals from different pathways
• Spread the signal along divergent pathways
Signaling networks control complex cell behaviors
• Complexity is much greater than described
• More signaling pathways available
• Interact in ways not described here
• Kinases often phosphorylate proteins of other pathways cross-talk
between pathways
• Some intracellular signaling molecules integrate information from
several sources
Model of signaling pathways involved in differentiation
of CD4+ T-cell
www.frontiersin.org
Convergence, divergence and cross talk
• Convergence
• Signals from different pathways can activate the same effector
• Divergence
• Signals from same ligand may diverge and activate many effectors
• Cross-talk
• signals can be passed back & forth between different pathways
Convergence
Convergence,
divergence and
cross talk
