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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen

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(1)

Medical Biotechnology Master’s Programmes

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

(2)

ENZYME-LINKED RECEPTORS

Tímea Berki and Ferenc Boldizsár Signal transduction

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

(3)

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)

(4)

Receptor classes I

Class 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-linked heterotetramers

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 kinase

insert; acidic domain V Vascular endothelial cell growth factor

(VEGF) receptor Contain 7 immunoglobulin-like domains as well as the kinase Insert domain

VI Hepatocyte growth factor (HGF) and scatter factor (SF) receptors

Heterodimeric like the class II receptors except that one of the two protein subunits is completely extracellular. The HGF receptor is a proto-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 rich

domain

(5)

Receptor classes II

Ligand Receptors Ligand Traps Accessory Receptors Smads

TGF-b TbR-II

TbR-I ALK5

Latency-associated polypeptide (LAP) Decorin

a2-macroglobulin

Betaglycan Smad2

Smad3 Smad4

Inhibin ActR-IIB

ALK4 Betaglycan Smad2

Smad3 Smad4

Activin ActR-IIB

ALK4 Follistatin Smad2

Smad3 Smad4 Nodal

GDF1 Vg1

ActR-IIB ALK4 ALK7

DAN

Cerberus Cripto Smad2

Smad3 Smad4

BMP2 BMP4 BMP7

BMPR-II ALK3 ALK6

DAN Cerberus Chordin/SOG Follistatin Noggin

Smad1 Smad5 Smad8 Smad4

BMP4 GDF5

ActR-IIB ALK3 ALK6

Chordin/SOG Follistatin Noggin

Smad1 Smad5 Smad8 Smad4

BMP7 ActR-IIB

ALK2

Chordin/SOG Follistatin Noggin

Smad1 Smad5 Smad8 Smad4

MIS

AMHR-II ALK2 ALK3 ALK6

Smad1 Smad5 Smad8 Smad4

TGF-b TbR-II

ALK1 Endoglin

Smad1 Smad5 Smad8 Smad4

(6)

Introduction

“ Complete ” receptor tyrosine kinase “ Incomplete ” receptor

Cytoplasmic non-receptor tyrosine kinase Adaptor

Signal Signal

(7)

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 family

II Insulin rec. family XI TIE family III PDGF family XII ROR family IV FGF family XIII DDR family V VEGF family XIV RET family VI HGF family (c-Met) XV KLG family VII Trk family XVI RYK family VIII Eph family XVII MuSK family

IX AXL family

(8)

Fibronectin III Leucine-rich Cysteine-rich

Acid-box Kinase

IG-like

VEGFR1 VEGFR2 VEGFR3 PDGFR

PDGFRβ CSF1R Kit Kit2

Ryk Torso

EGFR ErbB2 ErbB3 ErbB4

Met Ron Sea

TrkA TrkB TrkC INSR

IGF1R IRR

Axl Mer Sky

Eph Eck Eek Erk Elk Ehk1 Ehk2 Sek Hek Hek11 Cek-9 Myk-1 Myk-2

Ros FGFR1

FGFR2 FGFR3 FGFR4

Tie Tie2

DDR Ret Ror1 Torpedo

Ror2 Ltk Alk

EGF-like Cadherin

Factor VIII-like

Glicyne-rich Kringle C1r-like

Receptor tyrosine kinase family

(9)

Main steps of RTK activation

1 Ligand binding 2 Dimerization

3 Autophosphorylation

4 Signal complex (adapter proteins, kinases

etc.)

(10)

Dimerization of GF receptors

Plasma membrane

Cytoplasm

Juxtamembrane region Activation and catalytic loop (substrate precluding) C-terminal region Activation and catalytic loop (substrate accessible)

P P

P P

P P P

P

P P

ATP ATP

Dimerization

(11)

Autophosphorylation of RTKs

p120 Ras-Gap PLCg

Phosphotyrosine

Y559 Y581 Y716 Y741 Y751 Y771 Y1009 Y1021

Phosphotyrosine

Y992 Y1045 Y1068 Y1086 Y1148 Y1173

PDGFR

P P P

P P

P P

P P

P P P

P P

EGFR

P P P P

P

P P P

P P

Shc SLP7

6 Abl

Cbl PI3K

IRS-1

GRB2 SHP- SRC

1 STAT1 Crk

Nck

(12)

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.

(13)

Members of the signaling complex

SRC

PLCg

PKC

PI3K RAS

RAF

MEK MAPKs

Plasma membrane SOS

SHC GRB2

RSK FAK

Differentiation

Transcriptional regulation

Differentiation/Growth

Nucleus Y

Y Y

Y Y Y

Growth factor/Hormone

Receptor PTK

Cytoplasm

(14)

Ras-MAPK pathway

Elk-1

P P

Plasma membrane Cytoplasm RAS

SOS GRB2

Growth factor/Hormone

Receptor PTK

Active

RAS RAF

MEK1

ERK2

Adaptor

Guanine nucleotide

exchange factor (GEF)

GTP GDP

P P

MEK1

P P

ERK2

P P

ERK2

P

ERK2

P

P P

SRE Elk-1

Elk-1

P P

SRF Nucleus

AP-1

P

cFos

P +

?

Gene transcription

(15)

Parallel MAPK pathways

ERK pathway p38 pathway JNK pathway

Mitogens Stress/Cytokines

Ligands and activators

A-raf, B-raf, C-raf MEKK1, DLK, MLK2, ASK, TAK1, TAO, TAO2 MAPKKK

MEK1, MEK2 MEK3, MEK6 MEK4, MEK7

MAPKK

ERK1, ERK2, ERK5 ERK3, ERK4 p38a, b, d JNK1, 2, 3 MAPK

RSK1 RSK2 RSK3 RSK4

MSK1 MSK2

MNK1

MNK2

MK2 MK3

MK5B MK

PDK1

(16)

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

(17)

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

(18)

differentation

Ca2+

FoxO3 ER

Stat1/1

CREB TIF1A

C-Myc/

N-Myc Pax6

Elk-1 C-Fos

Ets UBF ETV1

HMGN1

ATF1 Histone

H3 SRF

TIF1A ETV1

ERa C-Fos Myt1 ATF4

MITF Nur77 Mad1 C/EBPβ

Ran BP3

Erk1/2 MSK1/2

BUB1 p90RSK

P27 KIP1

Erk1 MEK1 PKC

Erk1/2

MNK1/2 MEK1/2

B-Raf c-Raf

c-Raf PKA

PAK

Src PI3K

Fyn FAK

Tpl2/

Cot1

C-TAK1

MPK-1/2 cdc25 MPK-3

PP1/

PP2At

SOS

Bim C3G

SOS

SOS Ras

Rac

Rap1 PLCg

cPLA2

P14 MP1 IMP

PEA-15 PPARg

Spred

KSR 14-3-3

Shc FRS2

IRS GRB2

Pax CAS Tal

elF4B rpS6

Filamin A IkBa

CRK

TSC2 eEF2

Kinase DAPK

BAD GSK-3

METTL1 nNos

Ca2+

GRB2

PYK2

B-Raf

PD98059 U0126

Late endosome

Cell adhesion Transiation

control Ion channels,

receptors Heterodimer

Cytoskeletal proteins

Progression of cell cycle

Nucleus Cytoplasm

Ca2+

Ion channels RTKs

RTKs

Integrins

Spry

cAMP

p90RSK

Hivatkozások

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