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9 June 2011
Terms in this set (24)
Types of signals
Nucelar receptors (can be via cytopsmaic receptor): steroid hormones, thyroid hormones, vitamin D-stimulate mRNA-protein synthesis. Membrane receptors: transmitters, peptide hormones-activate cAMP and Ca2+ for phosphorylation to activate protein production and enzyme regulation.
Signal transduction themes
On/off processes, protein-protein interactions, protein-lipid interactions, crosstalk between signaling pathways
Types of signal classes
Receptor kinases (binds IGF to stimulate protein tyrosine or serine kinase for phosphorylatino mediated actions), receptor-linked kinases (GH, prolactin, cytokines-->receptor associated tyrosine kinases-->phosphorylation mediated actions), g-protein coupled receptors (peptides, neurotransmitters, prostaglandins-->second messenger, cytoplasmic protein kinases-->phosphorylation mediated actions-PMA), ligand gated ion channels (NT, AA-->ions-->non-phosphorylation mediated actions or cytoplasmic PK-->PMA)
G-protein coupled receptor (GPCR)-cAMP-PKA pathway activation
7 transmembrane domains, interacts with G-protein--> GTP-GDP phosphorylating g-subunit-->adenylyl cyclase activation-->ATP-cAMP. Off switch: phosphodiesterase transfers cAMP to AMP-->degradation. Caffeine inhibits off switch.
Regulation of GPCR
When GTP becomes GDP, Galpha will combine with -beta-gamma and will become inactive (off switch). Regulated via RGS (shortens duration of activity of system by stabilizing GDP).
Receptor phosphorylation by beta-ARK and recruitment of arrestin
Mechanism to turn off GPCRs. 1. phosphorylation by GRKs, prepares for arrestin binding. 2. Arrestin binding to receptor blocks further GP-mediated signalling, targets receptor for internalization by linking to clathrin, and redirects signaling to alternative GP-independent pathways. In addition to GPCRs, arrestins bind to other classes of cell surface receptors/signaling proteins.
Signals PIP2 which leads to IP3 (signals Ca release from ER) and diacyl-glycerol (DAG, which is embedded in membrane and leads to Ca via PKC)
Activated by ligand-bound receptor. Dimerization leads to autophosphorylated on the inside. Binding point for next protein on the pathway. SRC is made up of SH1-3. SH1 is tyrosine kinase. SH2 binds phosphorylated tyrosine. SH3 binds proline-rich domain.
EGFR Growth Factor Receptor
Severl tyrosines, each can be phosphorylated. Different signal depending on which phosphorylated. Ex: PLCgamma, Grb2, Shc. Must dimerize for activation
One of Grb2 that binds to Grb2. Grb2 binds to EGFR on one side and Sos on the other side. Sos activates ras (oncogene) which, through Raf, MAPK and ERKK activates nucleus.
Signal transduction targeted therapy
If we know how to target protein that leads to a pathological problem we can target antibodies to them or attack tyrosine kinase pathway we can have highly selective and low toxicity therapy.
Tyrosine Kinase Receptors as targets for therapy
Initiate multiple signaling pathways, convenient accessibility on cell surface for antibodies (don't need anything to enter cell), amenable to enzymatic blockade (kinase inhibitors)
Human EGF Receptor (HER) tyrosine kinase receptor family
We have 4 of these receptors to ellicit different response pathways. ErbB2/HER2 has TK activity but not ligand binding. ErbB3/HER3 has no TK activity but has ligand binding. 1 and 4 have TK and ligand activity. Lots of redundant possibilities. Works in a bowtie signalling network.
How does HER2 function without TK activity?
No ligand, but signal transduction requires dimerization with other HER receptor. Confirmation to bind and activate other receptor with its own ligand. More potent proliferation, migration and less apoptosis
1. Antibody: HER receptor target leading to receptor degradation or inactivation (ex: Herceptin). 2. Kinase inhibitor which blocks signal transduction inside cells. 3. Toxin conjugate (attached to ligand) to promote cell death. 4. Antisense or siRNA blocking protein synthesis (in development)
How do HER2/ErbB2 heterodimers promote cancer?
1. Slow dissociation of ligands from partner receptors as compared to homodimers. 2. Change in affinity of heterodimer with ErbB3 to additional ligands usually not recognized by ErbB3. 3. Receptor endocytosis inhibited and recycling enhanced because in HER1:HER2 dimers ubiquination is reduced (normal physiological conditions-->ubiquination of receptor by cCbl -->receptor degradation). 4. Phosphorylated ErbB2 bound to shc and activates MAPK and proliferation, Phosph-ErbB3 activates P13K and anti-apoptosis. Increased Erb2 expression=increased tumor aggression. Found in 20-30% of mammary tumors
Humanized andti-ErbB2 antibody. High affinity and specificity. 95% human, 5% murine. Decredased potential for immunogenicity. Increased potential for recruiting immune-effector mechanisms. Effect is degradation and downregulation of membrane HER2. Not a cure but inactivation of tumor and prolongation of life. Active alone and with chemo in FISH+ tumors (some breast (main), ovary, lung, pancreas and prostate cancers).
Protein-lipid interactions: Insulin Receptor Substrate (IRS)
Actie receptor phosphorylates IRS (tyrosine kinase substrate) which recruits active PI3 kinase through MAPK pathway. PIP2 gets another phosphate from PI3 kinase to become PIP3 for another signaling pathway.
Phosphotyrosine binding domains
SH3: proline-rich protein or membrane lipid PIP3. SH2 and PTB binds to phosphorylated tyrosine. PH binds to PIP3 to be allowed into cell.
Insulin regulation of PI3-kinase activation pathways
Insulin receptor has tyrosine kinase activity of IRS, eventually binds to PIP3 inside membrane, which activates PKB-->activation of insulin signaling. Leads to inhibition of gene expression, inhibition of lypolysis, stimulation of glycogen synthesis, protein synthesis, glucose transport.
Off switches of PI3K regulated pathways (IRS)
All phosphatases/kinases that inhibit activation. 1. PTP1B removes phosphate, 2. PTEN inhibits phosphorylation of PIP3, 3. SHIP dephosphorylates PIP3. 4. Inhibitory autokinase, 5. tags IRS1 for ubiquitination, 6. JAK/Stat deactivation
Role of PTEN in downregulating PI3K signaling
Second step: inhibits PIP phosphorylation. Specific Phosphatase and Tensin homologue deleted on chromosome 10-cancer . Inhibits growth and survival signal
GH/Cytokine activated JAK/STAT pathway
Signal Transducers and Activators of Transcription. Activated with dimerization. Kinase is part of receptor (autophosphorylate). Ex: EPO receptor, activates MAPK when erythropoietin binds which affects gene expression in the nucleus. STAT dimerizes through thte SH2 domains. STAT enters nucleus and binds DNA via exposed NLS (nuclear localization sequence). JAK can also bind to G-protein pathway receptor (though mainly cAMP) but can happen even with cAMP pathway is blocked. Crosstalk between TK pathway and Gprotein pathway.
Big picture of fibroblast growth factors pathways and tumor formation
Lots of signals through lots of pathways. Final outcome effect of all signalling pathway through crosstalk, not just dependent on one receptor.
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