Signal Trans Duct Ion 1- 2011
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Transcript of Signal Trans Duct Ion 1- 2011
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SENYALITZACI CEL.LULAR I CNCER
(TEMA 5)
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Introduction; Signal transduction pathways and Cancer.
Growth factors
Tyrosine Kinase receptors
MAP kinase cascades. RAS, ERK, JNK and p38 MAP Kinase
PI 3-kinase: PKB; mTOR, GSK3-, catenin
Other cascades: TGF- , STAT, FAK
Transcription Factors: fos, jun, myc
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Divide or not divide: a critical decision
Mitogens
Cell cycle controlers
Mitogens controlthe celular decisionto proliferate
ProliferationDifferentiationSurvival
ApoptosisSenescence
Celular decisions:
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M
G1
S
G2
R
G0
CDK4
cic D
CDK2
cic E
CDK2
cic A
CDC2
cic B
DE
AB
CDKs
niveles
de
prote
na
G1 S G2 M
SENYALS EXTERNES
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Figure 8.22 The Biology of Cancer( Garland Science 2007)
E2F
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GROWTH FACTOR
CDK
Cyc
synthesis
degradation
CKIs
T161
T14
Y15
KinasePhosphatase
Kinases
CaK Kap1
Wee1
Myt1
p21, p27, p57
binding to: cdk4-6/cycD
inhibition of: cdk2/cycE-A
p16, p15, p18, p19binding to: cdk4-6
inhibition of
Phosphatasecdc25
- Cyclin-CDK assembly - intracellular localization
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Proliferation = cell division + growth
Growth Factor
Growth Factor
growth
cell division
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Figure 6.4 The Biology of Cancer( Garland Science 2007)
Growth factor induce: cell cycle, growth, morphologic changes...
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Figure 6.2 The Biology of Cancer( Garland Science 2007)
Growth factors activates early genes
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Signal transduction involves proteinphosphorylation and protein interaction
A. 518 kinases; ~180 phosphatases.
B. ~One-third of all proteins areregulated by reversible phosphorylation.
C. Substrate targets:Kinase: ~15-20Phosphatase: ~50
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Fig. 2Hanahan and Weinberg
Cell 100:57
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-What are the signal transduction
pathways involved?-What are the targets of thesepathways?-How do these targets evoke changes
leading to cancer?
Frequently asked questions when studyingcancer cell signal transduction
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Growth Factor:are proteins that bind to receptor on the
cell surface with primary result of activating cellular
proliferationand or differentiationEpidermal Growth Factor (EGF)Platelet-Derived Growth Factor (PDGF)
Fibroblast Growth Factors (FGFs)Transforming Growth Factors-b TGFs-)
Transforming Growth Factor-a (TGF-)
Erythropoietin (Epo)
Insulin-Like Growth Factor-I (IGF-I)Insulin-Like Growth Factor-II (IGF-II)
Interleukin-1 (IL-1)
Interleukin-2 (IL-2)
Interleukin-6 (IL-6)Interleukin-8 (IL-8)
Tumor Necrosis Factor-a (TNF-)
Tumor Necrosis Factor-b (TNF-)
Interferon-g (INF-)
Colony Stimulating Factors (CSFs)
Citokines:
secreted primarily from leukocytes
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related to IGF-I and proinsulinpromotes proliferation of many cell
types primarily of fetal origin
variety of cellsIGF-II
related to IGF-II and proinsulin, also called
Somatomedin C
promotes proliferation of many cell
types
primarily liverIGF-I
at least 100 different family membersanti-inflammatory (suppressescytokine production and class II
MHC expression), promotes wound
healing, inhibits macrophage and
lymphocyte proliferation
activated TH1cells (T-helper)
and natural killer
(NK) cells
TGF-
promotes proliferation anddifferentiation of erythrocytes
kidneyErythropoietin
several related proteins first identified as
proto-oncogenes; trkA (trackA), trkB, trkC
promotes neurite outgrowth and
neural cell survivalNGF
at least 19 family members, 4 distinctreceptors
promotes proliferation of many cells;inhibits some stem cells; induces
mesoderm to form in early embryos
wide range ofcells; protein is
associated with
the ECM
FGF
related to EGFmay be important for normal wound
healing
common in
transformed
cells
TGF-
promotes proliferation ofmesenchymal, glial and epithelial
cells
submaxillary
gland, Brunners
gland
EGF
two different protein chains form 3 distinct
dimer forms; AA, AB and BB
promotes proliferation of connective
tissue, glial and smooth muscle cells
platelets,
endothelial cells,placenta
PDGF
CommentsPrimary ActivityPrincipal
SourceFactor
Growth Factors
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EGF (epidermal growth factor)
* 1962 Dr. Stanley Cohen. Allat de glndules submaxil.lar de ratol. 1986Premi Nobel
*pptid de 53-58 aa ( 6000 Da). Difereix segons espcie
* Processament: sntesi com a pre-pro-EGF (1200.000)
pro-EGF (9.000)EGF (6.045)
*Estructura: protena transmembrana. Sequncia hidrofbica, 3 ponts de
disulfur
PRO EGFN-
TMSP
preproEGF
22 978 1023 1207
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Familia de lepidermal growth factor
HB-EGF: Hepatin-binding EGF
AR: Amphiregulin
BTC-betacellulin
EPR-epigeregulin
TGFN-TMSP
preproTGF
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Maturation of EGF: role of metalloproteases
In many cellular systems, EGF-like factors undergo constitutive shedding in
the absence of any stimulation In addition to constitutive shedding,
shedding of many transmembraneproteins can be up-regulated by a range of
chemical stimuli such as phorbol esters, calcium ionophores, calmodulin
inhibitors........
A number of different subtypes of metalloprotease families including
ADAMs matrix metalloprotease and membrane type matrix metalloproteases (MT-MMPs)
have been implicated in the ectodomain shedding of transmembrane proteins including
EGFlike factors.
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Figure 5.12b The Biology of Cancer( Garland Science 2007)
Deregulaton of receptor:autocrine signaling
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Table 5.3 The Biology of Cancer( Garland Science 2007)
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Growth Factors as Oncogenes
v-sis carried by simian sarcoma virus is derived from PDGF,
and c-sis is amplified in glioma.
int-2 was identified as a MMTV integration is related to FGFand is amplified in human breast carcinoma.
hst was isolated from stomach cancer and is amplified
(along with int-2) in head and neck tumors.
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Figure 5.10 The Biology of Cancer( Garland Science 2007)
Structure of tyrosine kinase receptors
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Figure 5.15 The Biology of Cancer( Garland Science 2007)
Activation of tyrosine kinase receptor:
dimeritation & autophosphorylation
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Phosphorylation: a quick process
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Schlessinger, (2000)Cell 103, 211-225
Dimeric assembly of 2 FGF2:FGFR1 complexes. FGF2 is colored orange, Ig-like domain 2 of FGFR1 is colored green, and Ig-like domain 3 of FGFR1 is
colored cyan. [Plotnikov et al., Cell 98, 641 (1999)]
Dimeritation
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Three-dimensional structures of the
insulin receptor tyrosine kinase (IRK)IRK conformational change upon activation
loop phosphorylation. The N-terminal
lobe of IRK is colored white and the C-
terminal lobe is colored dark grey. The
activation loop (green) containsautophosphorylation sites Y1158, Y1162
and Y1163, and the catalytic loop
(orange) contains the putative catalytic
base, D1132. Also shown are the
unbound/bound ATP analog and
tyrosine-containing substrate peptide
(pink). [Hubbard, EMBO J. 16, 5572(1997)]
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Figure 6.9 The Biology of Cancer( Garland Science 2007)
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SH2: Src-homology 2 domain
1991: was originally defined in the sarcana retroviral
oncoprotein v-Fpssequence of around 100 aa (antiparallel -sheet between
two -helices)
bind to phosphotyrosine and between 3-6 residues C-
terminal
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Figure 6.8a The Biology of Cancer( Garland Science 2007)
SH2 is specific for P-tyrosine and flanking amino acid region
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Figure 6.10a The Biology of Cancer( Garland Science 2007)
Protein-protein interaction through
specific domains
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Table 5.2 The Biology of Cancer( Garland Science 2007)
transformation due to:
over-expression, point mutation,
truncation of ectodomain, gene fusion....
Alteration of tyrosine kinase receptor in human tumors
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presentaci: Dr. Maggi Coplin
OVER-EXPRESSION
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Figure 5.11 The Biology of Cancer( Garland Science 2007)
V-Erb, a trucated form of EGFR
truncation of ectodomain
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Figure 5.17 The Biology of Cancer( Garland Science 2007)
Gene fusion receptors
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Growth Factor Receptors in Leukemia
chronic myelomonocytic leukemia with t(5;12)
DZ ETS-DBDTEL
TMLigand Kinase
PDGFR
t(5;12) DZTEL- PDGFR Fusion
Kinase
PDGFR;
Must dimerize to transduce
a signal
TEL is a transcriptionfactor with a strongdimerization domain.
Dimerized in absense of ligand - always on
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Figure 5.12a The Biology of Cancer( Garland Science 2007)
Point mutation:
constitutive active receptor
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KIT mutations
GIST (gastrointestinal estromal tumours) Most KIT mutations effect
exon 11, others 9,13,17
The type of exon 11 deletion
may affect prognosis:deletions of codons 562 to579 (563-569 always
malignant)
Exon 11 mutations are more
likely to respond to iminitab
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Imatinib (Gleevec) a Tyrosine
Kinase Inhibitor Imatinib mesylate is a protein-tyrosine
kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase, the constitutiveabnormal tyrosine kinase created bythe Philadelphia chromosome
abnormality in chronic myeloid leukemia(CML).
Imatinib is also an inhibitor of thereceptor tyrosine kinases for platelet-derived growth factor (PDGF) and stemcell factor (SCF), c-kit, and inhibitsPDGF- and SCF-mediated cellularevents. In vitro, imatinib inhibitsproliferation and induces apoptosis ingastrointestinal stromal tumor (GIST)cells, which express an activating c-kitmutation