Signal Transduction
Perception and conveyance of information from outside the cell to the nucleus or other
sites within the cell, leading to a cellular response.
Signal transduction pathways should NOT be thought of in the same terms as
biochemical or metabolic pathways--they are very different. Signal transduction occurs
in response to a signal and consists of a series of post-translational modifications that
regulate the activity of proteins. The net result of this regulatory cascade is a change in
cell activity. This change in cell activity MIGHT involve the production of a product, such
as activation of the transcription of a gene. But it might not. It might just result in a
different cytoskeletal configuration, vesicle fusion (like in the slow block to polyspermy-response to a signal from sperm binding) or could result in the repression of a gene's
transcription. Lots of other responses are possible, including cell division, differentiation,
or death. So the easiest way to think about signal transduction pathways is simply as a
mechanism (cascade of posttranslational modifications) that regulates a cellular activity
or activities in response to a signal.
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receptors are the site of perception
ligand binding induces a conformational change in the receptor, leading to a
change in protein interactions and/or activities
o proteins may be recruited to, dissociated from, modified by, or modify, a
ligand-activated receptor
involves cascades of post-translational modifications that regulate the activities of
the proteins
I. Peptide Signals
• Cell surface receptors
IA. Receptors
IA1. Receptor Kinases (most growth factors, some peptide hormones)
• usually receptor tyrosine kinases (RTKs) in animals
• receptor serine/threonine kinases in plants
• single membrane spanning domain
• extracellular receptor domain
• cytoplasmic protein kinase domain
• ligand binding by the receptor domain activates the kinase domain
o dimerization a common mechanism
1A2. Other single-pass transmembrane receptors
• look like receptor kinases but without a kinase domain
• often associate with a cytoplasmic protein kinase
1A3. Multipass membrane spanning receptors
• e.g. Frizzled
o Wnt pathway
o 7 transmembrane receptor
IB. Signal transduction pathways
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most involve post-translational modification of proteins
o Protein phosphorylation / dephosphorylation a major mechanism
some utilize “2nd messengers”
o Intracellular signaling molecules produced in response to an external
stimulus
o Ca++, DAG, IP3, cAMP (e.g. figs 7.28, 7.29)
Many are modular
o many signal transduction proteins belong to families of proteins and
different family members are used in different pathways
o different combinations of the same proteins can be used for different
pathways
negative regulation is a common theme—many pathways are activated by
blocking a repressor
IB1. MAP kinase cascades
• MAP a transcription factor (but not the only one controlled by these pathways)
• MAP gets phosphorylated and activated by MAPKinase (MAPK)
o examples of MAPKs include ERK, JunKinase
• MAPK gets phosphorylated and activated by MAPKinaseKinase (MAPKK)
o MEK an example of a MAPKK
• MAPKK gets phosphorylated and activated by MAPKinaseKinaseKinase
(MAPKKK)
o Raf an example of a MAPKKK
• Each of these represents a multigene family
• Different MAPK pathways are associated with different receptors
• Can regulate cytoplasmic factors as well as transcription
IB2. G-proteins
• Active when bound to GTP, inactive when bound to GDP
• Examples include
o Ras—activates a MAP kinase cascade
o Rab—mediates membrane vesicle fusion
o Rac—regulates cytoskeletal activities
I.B.3. Jak-Stat pathway
• Jak = kinase
• Stat = Signal Transducer and Activator of Transcription
• Activated Jak phosphorylates Stat
• Phosphorylated Stat dimerizes and enters nucleus to activate transcription
• e.g. prolactin activates Jak-Stat pathway that activates casein gene transcription
I.B.4. PhospholipaseC
• some members regulated by phosphorylaton
• hydrolyze PIP2 to DAG and IP3
II. Steroid Signals (e.g. estrogen, testosterone) and molecules with similar properties
(retinoic acid, thyroid hormone)
• small molecules that freely pass through membranes
• receptors need not be localized on cell surface
A. Nuclear receptors
• transcription factors (activators or repressors)
• associate with “heat shock proteins” that inhibit receptor activity
• binding of steroid disrupts complex and activates the receptor
• some are cytoplasmically localized—steroid binding disrupts the HSP complex
and allows translocation into the nucleus where it can regulate gene transcription
• some are always nuclear localized and associate with HSPs in the nucleus until
steroid binding
III. Contact-dependent signal transducton
A. Integrins and ECM interactions
• Integrins are heterodimers of α and β subunits (each subunit a family and integrin
can be formed from various combinations of subunits)
• Interact with the ECM
• Interact indirectly with actin microfilaments of the cytoskeleton inside the cell
• Can also interact with intracellular signaling complexes
B. Notch
• Ligand binding induces conformational change
• This causes proteolytic cleavage
• The released fragment enters the nucleus and interacts with transcription factors
to regulate gene expression.
IV. Cellular responses
• mitosis / proliferation
• differentiation
o changes in gene expression
o migration
o stop dividing
• cell death
• response dependent on the target cell
o signal transduction molecules and transcription factors being expressed
V. Cells have to integrate many signals—most cells receive multiple signals and the
ultimate response depends on the combination of signals and the developmental
state of the cell
VI. Cross talk—activation of one signal transduction cascade by another
• different pathways converge (e.g. fig 6.40)
• same protein acts in multiple pathways—can “accidentally” trigger different
response
• some signals have more than one receptor
• some receptors recognize multiple signals
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“alternate” modes of receptor activation (e.g. cadherin activation of FGF receptorfig
VII. Specificity—how do cells distinguish different signals if so many pathways use the
same elements?
• e.g. in PC12 tissue culture cells, NGF induces neurite differentiation while EGF
induces proliferation
• both pathways activate the ERK MAPK
• how do the cells know the difference? One way may be through the association
of signal transduction proteins in signaling complexes (“signalsomes”)
VIII. Attenuation of signaling
• turning signal transduction off is as important as turning it on
• attenuation mechanisms are often initiated as part of the signal response
o dephosphorylation by phosphatases
o degradation by ubiquitination
o endocytosis—activated receptors often targeted to lysosomes
IX. Signal transduction pathways are involved in many cancers
• signal transduction pathways often regulate cell proliferation
• inappropriate activation of a pathway can lead to inappropriate cell proliferation
• e.g. mutations in β-catenin (fig 6.23 part 2)