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Cell signalling > Receptor Tyrosine Kinases > Flashcards

Receptor Tyrosine Kinases Flashcards

1
Q

Growth factor examples

Discovery

A 
EGFR
VEGF
PDGF
FGF
TGF
Produced by many tissue types unlike hormones

Nobel prize- Cohen realised EGFR phosphorylates endogenous proteins using isotopic ally labelled ATP

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2
Q

Growth factors for chronic wound repair

GF, target, trial

A

EGF, epithelium, venous ulcers. Proliferation and migration
FGF, endothelium, diabetic and venous ulcers
TGF-B, fibroblasts, venous ulcers and pressure sores. Fibroblast activity and chemotaxis, stops proliferation (opposite to EGF AND FGF)

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3
Q

Non receptor RTKs

A

32 in genome
FAK, JAK, SRC
Have kinase, SH2 domains etc.
Growth, proliferation, adhesion. Src and FAK are find at the Integrins complex

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4
Q

4 structural features of RTKs

A

Kinase
Regulatory
TM domain single
Extra cellular ligand

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5
Q

Activation of GFRs generic

How does FGF enhance ligand binding?

A

Activation lip blocks kinase activity
Insulin- stops ATP, in FGF prevents substrate
Dimerisation causes phosphorylation of lip
Kinase activity activated by reducing Km for ATP or substrate
Kinase increases transphosphorylation docking sites as well as effect Pi
FGF- 2 ligands simultaneous also to heparan sulphate (ECM) to enhance ligand binding

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6
Q

Crystallisation of EGFR

A

Space mission STS-47
Microgravity
Mass transport only under gravity
Growth instead occurs by diffusion of molecules
Greater size and reduced defect densities

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7
Q

Structure of VEGF family

Inhibitors of VEGF and disease

A

Angiogenesis
8 exons by alternative splicing, 5 different sized proteins
The growth factor is disulphide bonded homodimers
Can dimerise the RTKs, as site on each end
Plasmin cleaves the heparin binding domain at either end

Ranibizumab and pegaptanib- used to treat wet type macular degeneration

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8
Q

Structure of the insulin receptor

A

Heterodimers of alpha beta chains
Constitutive
Extra cellular domain is a covalently linked dimer (dimer of dimers)
Upon ligand binding, the domain still dock
Unfolding and activation of cytoplasmic domains

Insulin in the blood forms inactive hexamer

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9
Q

How insulin engages its binding site

A

Does not bind first leu repeat
Engages carboxyl tail chain which is remodelled onto the leu repeat
CT displaces the B chain C terminus away from the hormone core
Revels conformational switch

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10
Q

TGFB superfamily

A

SER/THR NOT TYROSINE
Isoforms 1-3
Actinin and inhibin have opposite effects on FSH release
BMP7- phosphorylates SMAD 1+ 5 promoting osteogenic genes and healing. Promotes messnchymal cells to bone and cartilage

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11
Q

Cell adhesion and cancer crosstalk

Cadherin in cancer

A

Integrins upregulate EGFR to promote snail which represses markers and starts EMT transition
Kindlin and EGFR link

Beta catenin in Wnt signalling

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12
Q

TGFB is paradoxical

A

Prevents EM transition
But modulates cell invasion, immunity and microenvironment

Activates tumour suppressors, activates Par6-P and snail and slug
Represses ID1 which blocks transcription factors
Promotes fibroblasts
Inhibits osteoblasts

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13
Q

Formation of mature TGFB

A

3 proteins, 3 genes
N terminal pro cleaved but still attached
Mature domains bind to form a dimer and latent complex
Proteolysis or conformational change released the disulphide bonded mature domains dimer
In one mature domain, 3 Cys form knot. 4 antiparallel beta sheets

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14
Q

TGFB signalling pathway

A

TGFB binding to either RIII then RII which recruits RI
RIII increases surface conc
Release of Ri Ser/THR activity
Phosphorylates SMAD3, exposes NLS
The MH2 domain of SMAD3 joins with SMAD4 and another SMAD3
The trimer thing binds importin to the SMAD3 NLS
Ran GTP dissociates importin
TFE3 associates with SMAD complex and binds promoter
Transcription of plasminogen activator inhibitor PAI-1
Dephos by nuclear phosphatases

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15
Q

Mutations in FGFR TM domain

A

Y373C- thanatophoric dysplasia and bladder cancer
G375C- achondroplasia
Hydrophobic -> polar can lift out of membrane

Dimer stability, membrane segment, extra cellular contacts, catalytic domain

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16
Q

Structure and function of intracellular RTK domain

A

FGFR- activation loop interfere with peptide binding not ATP
More general autoinhibition mechanism?
Phosphotyrosines
Serve as docking sites for SH2 proteins

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17
Q

Juxtamembrane region of EGFRs

A

Between the TM and kinase domain
JMA- self interactions, 2 antiparallel helices where Arg face membrane. Interact via a ridges and grooves interaction
Activation lip occludes and inhibits.
JmB forms a clamp between the N lobe of the receiver and the C lobe of the activator- this stabilises the activated form and brings the kinases into close proximity. Point mutations here stop activation
Kinases bind asymmetrically giving activator and receiver
JMA then forms the helical dimer (prevented by c terminal tails in inactive)

18
Q

The 4 types of EGFRs

A

HER1-4
HER2 doesn’t bind ligand, forms heterodimers
Enhances signalling, so higher efficacy of ligand binding less ligand needed
HER3 kinase dead
25% cancers have more her2
Herceptin prevents signalling complex and targets dgradarion
20k -> 600K

19
Q

Regulation and inhibition of EGFR

How does cancer resist this

A

EGFR is internalised and is then ubiquitinsted
Only one of family
T790M in ATP pocket makes resistant to first generation RTKIs which prevent ATP binding
Change to Met causes resistance because of steric hindrance of the Met and RTKIs

20
Q

Protein tyrosine phosphatases

A

Polymorphisms cause type 1 and 2 diabetes
Regulators of liver homeostasis and mediate pancreatic B cell death
PTB1B targets EGFR
107 PTPs compatible with 90 TKs

21
Q

Regulation of PTP by dimerisation

A

Ligand binding inhibits the PTPs by dimerisation
Inhibition of catalytic D1 PTP domains
Wedge motif of one D1 occludes active site of other
Essentially opposite of RTKs

22
Q

PTPs in disease

A

PTPN1- non insulin dependent diabetes

PTPN2- T cell leukaemia

23
Q

Tandem kinase domain EGFR

A 
Glioblastoma
Elevated basal autophosphorylation
Resistant to competitive inhibition
Knock outs of either domain show patterns of a constitutively active
N site- basal activity
C site- ligand responsiveness
24
Q

EGFR gene in brain tumours

A

3’ end in glioblastomas
Deletions of 255 bases near cytoplasmic domain
vIVa and vIVb deletion of internal segment distal to the kinase domain. C terminus surface inhibits kinase so the deletion is activating

Exons 2-7 deletions -> TYPE III MUTANT
Activated no ligand
truncated receptor no N terminus

25
Q

C terminal deletions of EGFR- how come they are activating?

A

Viva and vIVb deletions enhance basal activity

Delete negatively charged segment of the C end that forms an inhibitory surface with the kinase

26
Q

V-Erb

A

V-erbB gene truncated ligand domain of chicken
Type III (N loss) and type IV mutant (C loss)
Chicken erythroblastoma virus
Aids uncontrolled cell growth
Always active, no inhibition and no ligand binding

27
Q

Retrovirus associated oncogenes table

A

.

28
Q

Chicken sarcoma virus discovery

What special gene does it have?

A

Payton rouse 1910
Rouse sarcoma virus
Filtrate of sarcoma could induce cancer
Allowed scientists to induce tumours at will

4th gene encoding v-src
Triggers uncontrolled growth
More cells for fresh infection

29
Q

Human cancers caused by viruses

How did viruses help undstanding?

A

Cervical and hepatomas
Although viruses were disproved, the mechanisms by which they induced cancer helped to identify genes
Physical and chemical agents

30
Q

Src domain structure

Activation

A

SH1- catalytic, kinase
SH2- binds to C terminus. Binds pY-e-e-l sequence
SH3- poly proline helix binding e.g. PI3K. R-P-L-P-V-A

Activation causes dephos of the Tyr of the C tail (needs phosphatase)
Opening of Sh2 and sh3
Autophosphorylation of T527

31
Q

PH domain

A

Binds PIP3

32
Q

The grb2 and shc bridging proteins

2 types

A

RTK -> SH2 of Grb2
Two SH3s of Grb2 -> poly proline of Sos
Sos acts as a GEF for RAS

OR

Shc pY binds Grb2 -> Sos -> Ras

33
Q

Ras Raf MAPK pathway

A 
Ras G12V always active
Sos
Ras
PI3K and MAPKKK (Braf)
MAPKK (Mek1/2)
MAPK (Erk), transcription factor. Cross talk with Integrins, as FAK can activate MAPK
34
Q

Diseases of Ras Raf MAPK pathway

A

EGFR of expression- pancreatic and colorectal
Ras- pancreatic, colon, lung
MAPKKK- melanoma

35
Q

How does Grb actually activate Sos theory?

A

Pawson 1990
Just forces sos to relocate
Cells lacking Grb2 rescued by giving Sos an SH2 domain
Proved just recruits Sos to where Ras is

36
Q

The different MAPK routes

A

RAS RAF -> proliferation
MLK, MKK47, JNK -> stress response (stress activated protein kinases) regulates c-Jun for proliferation
MLK, MKK36 p38 -> apoptosis

37
Q

Immediate vs delayed genes

A

Immediate- pre existing TFs. B and Y actin, tropomyosin and fibronectin. Remodelling and moving GLUT transporters

Delayed- MAPK pathway to create new TFs before gene activation

38
Q

Two pathways of PI signalling

A

PI -> PIP2 by PIKs to recruit talin
PI3K converts PIP2 -> PIP3
Or PIP2 can be broken down to IP3 and DAG BY PLC (GPCR cross talk)

39
Q

PI3K structure

A

Ras binding domain recruits
Starts to convert Pip2->3
Makes PH sites
Creates site for Plc, AKT and btk

40
Q

The PI3K AKT pathway
Regulation
How is cancer formed

A

AKT docks to pip3 with Its ph domain
Then doubly phosphorylated by PDK1 and PDK2
Uses Foxo transcription factor
Affects VEGF
Drives VEGF in tumour cells for angiogenesis
PTEN is a tumour suppressor, converts pip3 to pip2

PTEN inactivity or pi3k hyperactivity

41
Q

Pi3k can either lead to
AKT
Or
RHO-GEF

A

Rho is used as part of actin
Integrins can regulate this- FAK acts on Grb2 -> sos -> Ras
But cdc42 and Rac are part of the Ral signalling

42
Q

Alterations in cell signalling

Activating, over expression and inactivation examples

A 
Active mutations
AKT (e17k)
Ras (g12 and q61)
RTK
Src
MAPK

Over expression
Her2

Defective
PTEN
Phosphatases
RTK

Cell signalling (5 decks)

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