Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
ENZYME-LINKED RECEPTORS
Tímea Berki and Ferenc BoldizsárSignal transduction
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
TÁMOP-4.1.2-08/1/A-2009-0011
Receptors with enzyme activity• Receptor Tyrosine Kinases (RTK)
– e.g. PDGF, insulin, EGF, VEGF and FGF receptors• Receptor Tyrosine Phosphatases
– e.g. CD45 (cluster determinant-45) protein of T cells and macrophages
• Receptor Guanylate Cyclases– e.g. natriuretic peptide receptors
• Receptor Serine/Threonine Kinases– e.g. activin and TGF-β receptors
• Tyrosine-Kinase Associated Receptors: receptors that associate with proteins that have tyrosine kinase activity (Cytokine Receptors)
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Receptor classes IClass Examples Structural Features of Class
I EGF receptor, NEU/HER2, HER3 Cysteine-rich sequences
II Insulin receptor, IGF-1 receptor Cysteine-rich sequences; characterized by disulfide-linkedheterotetramers
III PDGF receptors, c-Kit Contain 5 immunoglobulin-like domains; contain the kinase insert
IV FGF receptors Contain 3 immunoglobulin-like domains as well as the kinaseinsert; acidic domain
V Vascular endothelial cell growth factor(VEGF) receptor
Contain 7 immunoglobulin-like domains as well as the kinaseInsert domain
VI Hepatocyte growth factor (HGF) and scatterfactor (SF) receptors
Heterodimeric like the class II receptors except that one of the twoprotein subunits is completely extracellular. The HGF receptor is aproto-oncogene that was originally identified as the MET oncogene
VII Neurotrophin receptor family (TRKA, TRKB,TRKC) and NGF receptor
Contain no or few cysteine-rich domains; NGFR has leucine richdomain
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Receptor classes IILigand Receptors Ligand Traps Accessory Receptors Smads
TGF-b TbR-IITbR-IALK5
Latency-associated polypeptide (LAP)Decorina2-macroglobulin
Betaglycan Smad2Smad3Smad4
Inhibin ActR-IIBALK4
Betaglycan Smad2Smad3Smad4
Activin ActR-IIBALK4
Follistatin Smad2Smad3Smad4
NodalGDF1Vg1
ActR-IIBALK4ALK7
DANCerberus
Cripto Smad2Smad3Smad4
BMP2BMP4BMP7
BMPR-IIALK3ALK6
DANCerberusChordin/SOGFollistatinNoggin
Smad1Smad5Smad8Smad4
BMP4GDF5
ActR-IIBALK3ALK6
Chordin/SOGFollistatinNoggin
Smad1Smad5Smad8Smad4
BMP7 ActR-IIBALK2
Chordin/SOGFollistatinNoggin
Smad1Smad5Smad8Smad4
MIS
AMHR-IIALK2ALK3ALK6
Smad1Smad5Smad8Smad4
TGF-b TbR-IIALK1
Endoglin
Smad1Smad5Smad8Smad4
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Introduction
“Complete” receptor tyrosine kinase “Incomplete” receptor
Cytoplasmicnon-receptor
tyrosine kinase
Adaptor
Signal Signal
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Receptor tyrosine kinase (RTK) families• 90 unique Tyr kinases in the human genome, 58 are RTKs• Growth factor, cytokine and hormone receptors• Classes:
I EGFR family (ErbB) X LTK familyII Insulin rec. family XI TIE familyIII PDGF family XII ROR familyIV FGF family XIII DDR familyV VEGF family XIV RET familyVI HGF family (c-Met) XV KLG familyVII Trk family XVI RYK familyVIII Eph family XVII MuSK familyIX AXL family
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Fibronectin IIILeucine-rich
Cysteine-richAcid-box
KinaseIG-like
VEGFR1VEGFR2VEGFR3
PDGFRPDGFRβCSF1RKitKit2
Ryk TorsoEGFRErbB2ErbB3ErbB4
MetRonSea
TrkATrkBTrkC
INSRIGF1RIRR
AxlMerSky
EphEckEekErkElkEhk1Ehk2SekHekHek11Cek-9Myk-1Myk-2
RosFGFR1FGFR2FGFR3FGFR4
TieTie2
DDR Ret TorpedoRor1Ror2
LtkAlk
EGF-likeCadherin
Factor VIII-likeGlicyne-rich Kringle
C1r-like
Receptor tyrosine kinase family
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Main steps of RTK activation
1 Ligand binding2 Dimerization3 Autophosphorylation4 Signal complex (adapter proteins,
kinases etc.)
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Dimerization of GF receptors
Plasma membrane
Cytoplasm
Juxtamembrane region C-terminal regionActivation and catalytic loop (substrate precluding)Activation and catalytic loop (substrate accessible)
PP
PP
PP
PP
P PATP ATP
Dimerization
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Autophosphorylation of RTKs
p120Ras-Gap
PLCg
PhosphotyrosineY559Y581Y716Y741Y751Y771
Y1009Y1021
Phosphotyrosine Y992Y1045Y1068Y1086Y1148Y1173
PDGFR
PP
PPP
PP
PPP
PP
PP
EGFR
PPPPP
PPPP
P
Shc SLP76
Abl
CblPI3K
IRS-1
GRB2 SRCSHP-1
STAT1
Crk
Nck
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Members of the initial signal complex • Enzymes/transcription factors:
Src/Syk family kinases, SHP-1, PLCg, Sos, Vav, RasGAP, STAT1 etc.• Adaptors/regulators:
Grb2, SLP-76, SOCS1, Nck, Shc, Crk-L, p85 etc.• Adaptors/docking proteins:
FRS2, IRS1, DOK1 etc.
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Members of the signaling complex
SRC
PLCg
PKC
PI3K RAS
RAF
MEK
MAPKs
Plasma membrane
SOSSHC GRB2
RSK
FAK
Differentiation
Transcriptional regulation
Differentiation/Growth
Nucleus
YY
YYY
Y
Growth factor/Hormone
Receptor PTK
Cytoplasm
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Ras-MAPK pathway
Elk-1 PP
Plasma membrane
CytoplasmRAS
SOSGRB2
Growth factor/Hormone
Receptor PTK
Active
RAS RAF
MEK1
ERK2
AdaptorGuanine
nucleotideexchange
factor(GEF)
GDPGTP
PP
MEK1 PP
ERK2 PP
ERK2 PPERK2P
P
SRE
Elk-1Elk-1 P
P
SRF
Nucleus
AP-1
PPcFos
+
?
Gene transcription
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Parallel MAPK pathwaysERK pathway p38 pathway JNK pathway
Mitogens Stress/CytokinesLigands andactivators
A-raf, B-raf, C-raf MEKK1, DLK, MLK2, ASK,TAK1, TAO, TAO2MAPKKK
MEK1, MEK2 MEK3, MEK6 MEK4, MEK7MAPKK
ERK1, ERK2, ERK5 ERK3, ERK4 p38a, b, d JNK1, 2, 3MAPK
RSK1RSK2RSK3RSK4
MSK1MSK2
MNK1
MNK2
MK2MK3
MK5BMK
PDK1
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MAPK-activated kinases (MKs)• RSK (ribosomal S6 kinases)
cytoplasmic (initiation factors of translation, apoptosis machinery, oestrogen rec., Sos), phosphorylated form can translocate to nucleus (ATF4, c-Fos, SRF)
• MSK (mitogen- and stress-activated kinases )in nucleus (CREB, histone H3, HMGN1, ATF1)
• MNK (MAPK-interacting kinases)translation initiation complex
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Turning-off the pathway
• Phosphatases PTP1B, SHP1/2, DEP1• Phosphorylation of GEF (Sos)
decreases the affinity to the adapter (Grb2)• Removal of cell surface receptors by
endocytosis
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MAPK/ERK in growth and differentation
Ca2+
FoxO3 ER
Stat1/1
CREB TIF1A
C-Myc/N-MycPax6
Elk-1
C-Fos
Ets
UBF
ETV1
HMGN1
ATF1
Histone H3
SRF
TIF1AETV1
ERa C-Fos
Myt1ATF4
MITF Nur77
Mad1
C/EBPβ
Ran BP3
Erk1/2MSK1/2BUB1p90RSKP27 KIP1
Erk1
MEK1
PKC
Erk1/2
MNK1/2
MEK1/2
B-Raf c-Raf
c-RafPKA
PAKSrc
PI3KFynFAK
Tpl2/Cot1
C-TAK1
MPK-1/2
cdc25
MPK-3
PP1/PP2At
SOS
Bim
C3G
SOSSOS Ras
Rac
Rap1 PLCg
cPLA2
P14MP1
IMP
PEA-15
PPARg
Spred
KSR
14-3-3
ShcFRS2IRS
GRB2Pax
CASTal
elF4B
rpS6
Filamin A
IkBa
CRK
TSC2eEF2KinaseDAPK
BAD
GSK-3
METTL1 nNos
Ca2+
GRB2
PYK2
B-Raf
PD98059U0126
Late endosome
Cell adhesion
Transiationcontrol
Ion channels,receptors
Heterodimer
Cytoskeletalproteins
Progression of cell cycle Nucleus
Cytoplasm
Ca2+Ion channels
RTKs
RTKs
Integrins
Spry
cAMP
p90RSK
