Download Signaling

Cell Communication-II
(Fall 2010)
Pin Ling (凌 斌), Ph.D.
Department of Microbiology & Immunology, NCKU
ext 5632; [email protected]
Reference:
“Mechanisms of Cell Communication”, The Cell (5th
edition), Chapter 15
Outline
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General principles of cell communication
Signaling through G-protein-coupled cell
surface receptors (GPCRs) and small
intracellular mediators
Signaling through enzyme-coupled cellsurface receptors
Signaling pathways dependent on regulated
proteolysis of latent gene regulatory proteins
Signaling in plants
Six major classes of enzyme-coupled
receptors
1. Receptor Tyrosine Kinases (RTKs)
2. Tyrosine kinase-associated receptors: No intrinsic
enzyme activity.
3. Receptor Ser/Thr kinases
4. Histidine-kinase associated receptors :
two-component signaling pathway
5. Receptor guanylyl cyclases
6. Receptor Tyr phosphatases
RTK Subfamilies (16):
60 human RTKs
Some growth factors or
cytokines act via RTKs
Signaling via RTKs
1. Activated RTKs phosphorylate themselves.
2. Phosphorylated Tyr residues on RTKs
=> Docking sites
3. Proteins w/ SH2 domain (PTB domain) bind to
phophorylated Tyr resides.
4. Ras, a family of monomeric GTPase, acts downstream
of many RTKs.
5. Ras activates a MAPK signaling module via adaptors &
GEFs.
Activation of RTKs via dimerization
Intracellular domains of activated
RTKs provide “docking sites’
Binding of SH2-containing proteins
to activated PDGF receptor
Figure 15-55a Molecular Biology of the Cell (© Garland Science 2008)
SH2 domains recognize phospho-Tyr in
the context of flanking sequences
Ras superfamily of monomeric GTPases
Sev RTK activates Ras in the fly
Ras activates the MAPK pathway
Activation of ERK/MAPK at various
intracellular compartments-I
Scaffold proteins in formation of
signaling complexes
Rho family GTPases couple surface
receptors to the cytoskeleton
The downstream pathways activated
by GPCRs & RTKs
PI3K (Phosphoinositide 3-kinase)
Signaling
1. PI3K is involved in downstream pathways of many
“Growth Factor Receptors”.
2. PI3K mainly phosphorylates inositol phospholipids
=> Docking sites on the plasma membrane.
3. PI3K activates the downstream AKt-mTOR pathway
=> Regulate cell survival & proliferation.
4. Deregulation of this pathway is often found in many
cancer cells.
Generation of PI docking sites by
PI3K
Cell survival via PI3K signaling
Cell growth via PI3K signaling
Tyrosine kinase-associated
receptor signaling
1. Many cell surface receptors depend on Tyr
phosphorylation but lack a Tyr kinase domain,
e.g. Cytokine receptors, Integrins, …etc
2. These receptors act through Cytoplasmic Tyrosine
Kinases, e.g. Src family kinases, FAK, ….etc.
3. Cytokine receptor activate the JAK-STAT pathway.
4. Tyr Phosphatases reverse Tyr phosphorylation on
various Tyr-phosphorylated proteins.
5. Tyr phosphatases have transmembrane & cytoplasmic
forms.
Cytokine signaling via the JAKSTAT pathways
Cytokine Receptor signaling via
the JAK-STAT pathways-II
Table 15-6 Molecular Biology of the Cell (© Garland Science 2008)
Transforming growth factor-b
(TGFb) Superfamily
1. TGFb superfamily consists of various mediators to
regulate cell proliferation, specification &
differentiation, e.g. TGFb/activin family, BMP (bone
morphogenetic protein) family.
2. All these mediators act via Ser/Thr kinase-coupled
receptors.
3. Activated receptors trigger the Smad pathway.
TGF-beta signaling pathway
Ser/Thr and Tyr protein kinases
are structurally related
Bacterial chemotaxis via Histidine
kinase-associated receptors
1. In bacteria, chemotaxis response is mediated by
Histidine kinase associated receptors.
2. These receptors activate a two-components signaling
pathway, also seen in yeasts & plants.
3. Histidine kinase-associated chemotaxis receptors
regulates flagella movements in a straight line or
tumbling.
Flagella movement during E.
Coli swimming
Chemotaxis
receptors
control flagella
movement
CheW: Adaptor
CheA: His kinase
CheY: Effector/
Phosphatase
Outline





General principles of cell communication
Signaling through G-protein-coupled cell
surface receptors (GPCRs) and small
intracellular mediators
Signaling through enzyme-coupled cell-surface
receptors
Signaling pathways dependent on regulated
proteolysis of latent gene regulatory
proteins =>Irreversible
Signaling in plants
Signaling via Notch Receptor
Protein
1. Notch signaling is involved in regulating cell fates &
development.
2. Role of Notch in nerve cell production:
Neighbor cell |= Precursor cell => Nerve cell
3. Signaling between adjacent cells via Notch & Delta
(or other related ligands).
4. Notch is a single-pass transmembrane protein
undergoing proteolytic process to function.
5. Deregulated Notch signaling is often found in cancer
development.
“Lateral inhibition” of nerve cell
development via Notch signaling
Proteolytic cleavage of Notch & its
signaling
Wnt/b-Catenin signaling
Activation of NF-kB pathway by
TNFa
Negative feedback control
& NF-kB oscillations
Outline





General principles of cell communication
Signaling through G-protein-coupled cell
surface receptors (GPCRs) and small
intracellular mediators
Signaling through enzyme-coupled cell-surface
receptors
Signaling pathways dependent on regulated
proteolysis of latent gene regulatory proteins
=>Irreversible
Signaling in plants
Signaling in Plants
1. Multicellularity & Cell communication evolved
independently in Plants & Animals.
2. Receptor Ser/Thr kinases are the largest family in
plants.
3. Various plant hormones (growth factors) regulate
plant development, e.g. ethylene, Auxin,….etc.
4. Signaling in plants mainly come from genetic studies
on Arabidopsis.
Divergence of plant & animal
lineage
Clavata1/Clavata2 (Clv1/Clv2) : Leucinerich repeat receptor (LRR) kinases
Ethylene-mediated
growth control:
1. Promote fruit ripening,
leaf abscission, &
senescence.
2. Germinating seedling:
(1) Thicken its stem
(2) Shield its tip of the
shoot
(3) Avoid obstacle
Ethylene Signaling Pathway
Raf-like
Photochromes mediate a light response
“Discussion” to be continued