tyrosine kinases
DESCRIPTION
Tyrosine kinases. http://msbl.helsinki.fi/tkseminar. Biological responses. Activation of Gene expression. Signal trans- duction. Signaling molecules. Producer cell. RNA. Receptor binding. Target cell. proliferation, differentiation, migration, metabolism, etc. - PowerPoint PPT PresentationTRANSCRIPT
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Michael Jeltsch
Tyrosine Tyrosine kinaseskinaseshttp://msbl.helsinki.fi/tkseminar
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Producercell Target
cell
Receptor binding
Signaling molecules
Signal trans-duction
Activation ofGene expression
proliferation, differentiation, migration, metabolism, etc.proliferation, differentiation, migration, metabolism, etc.
RNA
Biological Biological responsesresponses
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Cell surface Cell surface receptorsreceptors
ion-channel-linked
guanylylcyclases
tyrosinekinases
tyrosine kinaseassociated
tyrosinephosphatases
serin/threoninekinases
enzyme-linked G-protein-linked
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extracellular
juxtamembranetransmembrane
tyrosine kinase
carboxy-terminal tail
a
ligand bindingNH2
COOH
ATP
substratebinding
Receptor Tyrosine Receptor Tyrosine KinasesKinases
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Michael Jeltsch
VEGF xVEGF xVEGF-R1VEGF-R1
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ssss
ss
ss
EGF-R IGF-1-R FGF-RPDGF-R VEGF-R3
RTK RTK subclassessubclasses
I II III IV
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Modular structure of EC Modular structure of EC domainsdomains
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RTK RTK ligandsligands
• Some RTKs need two ligands for activation
• Extracellular matrix components (HSPGs)
• Membrane-bound proteins (ephrins)
• Cytokines (EGF, FGF, CSF-1, insulin)
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a
a
aa
PPPPPP
Signaling through an RTKSignaling through an RTK
aa
PPPPPP
a
a
a
a
a
a
a
a
a
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Dimerization or oligomerizationDimerization or oligomerization
• Bivalent ligand(e.g. VEGF, PDGF)
• Ligand-induced conformational change(probably EGF)
• Intracomplex conformational change(e.g. insulin)
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Transmembrane signal Transmembrane signal transfertransfer
• Exact mechanism unknown• Same or similar mechanism for all
RTKs (evidence from hybrid receptors)
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AutophosphorylationAutophosphorylation
• Purposes:- Regulation of tyrosine kinase activity- Recruitment of signaling molecules
• Specific Tyr residues, usually outside thetyrosine kinase domain (juxtamembranedomain, cytoplasmic tail, kinase insert)
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• SH2 (Src-homolgy 2)
• WW
• SH3 (Src-homolgy 3)• PH (pleckstrin homology)/FYVE
• PTB (phosphotyrosine binding)
Signaling proteins are modular moleculesSignaling proteins are modular molecules
SH2 PTB SH3 PH/FYVE PZB WW
• PDZ
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SH2 (Src-homology 2)/SH2 (Src-homology 2)/PTB (phosphotyrosine binding)PTB (phosphotyrosine binding)
• Bind to PY (and sometimes Y)• Specificity is achieved through the context• SH2: 1-6 amino acids C-terminal to PY• PTB: 3-5 amino aids N-terminal to PY (or Y)
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SH3 (Src-homology 3)SH3 (Src-homology 3)
• Binds to proline motif PXXP
WWWW
• Binds to proline motif PXPX
SH3 & SH3 & WWWW
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PH (pleckstrin homology)/FYVEPH (pleckstrin homology)/FYVE• PH domain binds to phosphoinositides (membrane-
localization)• FYVE domain binds specifically PtdIns-3-P
PDZ (PSD-95, DDLP, ZP1)PDZ (PSD-95, DDLP, ZP1)• Bind to hydrophobic C-terminal strtches of target proteins
PH/FYVE/PDZPH/FYVE/PDZ
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SH2PTB
P
P
PH/FYVE SH3 WW PDZ Enzymaticactivity
KinasesPhosphatasesPLC-Ras-GAPRho-GRF
Cellular Targets
membrane
Assembly of a specific signaling Assembly of a specific signaling complexcomplex
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Myristyl. PTB
PH
TM P P P P P
P P P P P P
P P P
Membranelocalization
Receptorbinding Tyrosines
PP
P
FRS2
Dos
LAT
Indirect recruitment is the main recruitment methodfor some receptors (insulin receptor, FGF receptors)
Docking Docking proteinsproteins
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Topics in activation of effector Topics in activation of effector proteinsproteins
1. Activation by Membrane Translocation
2. Activation by a Conformational Change
3. Activation by Tyrosine Phosphorylation
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1. Membrane translocation
2.ConformationalChange 3. Tyrosine Phosphorylation
Activation of signaling molecules: PDGF Activation of signaling molecules: PDGF receptorreceptor
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Intracellular Signaling Intracellular Signaling PathwaysPathways
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Signal Signal TerminationTermination
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• Ligand-induced oligomerization orconformational change
• Autophosphorylation/crossphosphorylation• Recruitment of signaling
molecules tophosphorylated tyrosines (“signalingcomplexes”)• Termination of Signaling (endocytosis)
3 Steps to 3 Steps to activationactivation
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Intracellular vs. Transmembrane Receptor Tyrosine Intracellular vs. Transmembrane Receptor Tyrosine Kinases:Kinases:
Phylogenetic tree of tyrosine kinasesPhylogenetic tree of tyrosine kinases
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Cytoplasmic Tyrosine Cytoplasmic Tyrosine KinasesKinases
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Tyrosine kinase-derived Tyrosine kinase-derived oncogenesoncogenes
oncogene retrovirus cellular counterpart
v-src Rous sarcoma c-srcv-erbB avian erythroblastosis EGF receptorv-fms McDonough feline
sarcomaCSF-1 receptor
v-kit feline sarcoma SCF receptorv-abl Abelson murine
leukemiac-abl
v-sis simian sarcoma PDGF
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ss
VEGF-R3
Dominant Negative Dominant Negative Receptors:Receptors:
VEGFR-3 mutations in hereditary lymphedema
S641P
P1114L
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Further Further readingreading
Schlessinger, J. (2000): Cell Signaling by Receptor Tyrosine Kinases.Cell, Vol. 103, 211-225.