3. 7 Growth factors Flashcards
1
Q
growth factors
A
are like protooncogenes
2
Q
cell growth occurs viea
A
auto,
para, and
endocrine actions
3
Q
auto, para, and endocrine actions work through
A
intrinsic kinase activity (mostly tyrosine kinase),
no kinase activity,
G protein-linked
4
Q
cell growth requires
A
more than one stimulus/growth factor to grow
5
Q
No growth factors results in
A
apoptosis
6
Q
some growth factors results in
A
survival
7
Q
other growth facotrs results in
A
division
8
Q
EGF and TGFalpha are
A
epidermal growth factor and transforming growth factor alpha are part of the EGF family and share a common receptor with intrinsic tyrosinge kinase activity
9
Q
EGF and TGF alpha stimulate
A
a variety of epithelial and mesenchymal cells to proliferate
10
Q
HGF
A
hepatocyte growth factor/scatter factor
11
Q
HGF receptor
A
c-met, a frequently mutated protooncogene that has tyrosine kinase activity
12
Q
HGF is made by
A
mesenchymal cells
13
Q
HGF stimulates
A
stimulates several types of epithelial cells including hepatocytes and bile duct epithelial cells
14
Q
HGF promotes
A
embryonic development and scattering/migration of cells
15
Q
VEGF
A
vascular endothelial growth factor
16
Q
VEGF family
A
A B C D
17
Q
VEGF is an inducer of
A
blood vessel formation in embryogenesis wound healing and tumor formation
18
Q
VEGFR -1, 2, 3
A
3 VEGF receptors with tyrosine kinase activity
19
Q
VEGFR-2
A
on endothelial cells,
binds VEGF-A,
main role is angiogenesis
20
Q
VEGF-C and D bind to
A
VEGFR 3 and promote lymphatic development
21
Q
PGF - Platelet derived growth factor sturcture
A
2 chains of A and B
22
Q
PGF isoforms
A
AA,
AB,
BB
23
Q
PGF C and D
A
recently discovered
24
Q
PDGFR alpha and beta
A
receptors with tyrosine kinase activity
25
PDGF is made by
platelets,
macrophages,
endothelial cells
26
PDGF induces
migration and proliferation of fibroblasts,
smooth muscle cells,
and monocytes
27
Fibroblast Growht factor is best characterized
acidic -: aFGF or FGF1,
| basic - bFGF or FGF2
28
FGF family has
10 members
29
FGF can associate with
heparan sulfate in ECM
30
FGF receptors
intrinsic tyrosine kinase activity
31
FGF is involved in
angiogenesis,
wound healing,
myocyte and blood vessel development,
hematopoesis
32
Transforming Growth factor beta family
TGF beta 1, 2, and 3;
BMPs
activins
inhibins
33
Most widespread TGF
TGF beta 1
34
TGF beta 1 is made by
macrophages,
endothelial cells (Ecs?),
lymphocytes and others
35
TGF receptors
type I and type II receptors with serine/threonine kinase activity
36
TGF receptor binding
binds type II first then complexes with type I
then phosphorylates Smad faimily preteins
that transduce signal
37
Smad
potent growth inhibitory signal and loss is associated with unregulated growth and neoplasia
38
Pleitrophic effects of TGF beta depend on
type, concentration, and co factors
39
TGF beta functions
inhibits proliferation of epithelial cells,
upregulates cell cycle inhibitors in some cells,
stimulates proliferation of fibroblasts and smooth muscel cells,
stimulates fibrosis,
anti-inflammatory
40
receptors with intrinsic kinase activity
most growth factor
41
receptors w/o intrinsic kinase activity that recurit kinases
cytokines
42
7TM gprotein coupled receptors
histmaine,
chemotactic,
signals,
epinephrine
43
Steroid hormone like receptors
```
in cytosol and nucleus:
steroids,
Vit D,
retinoids,
PPARs
```
44
receptor binding causes
receptor anchoring and aggregation
45
cascade pathways associated with tyrosine kinase
Ras-GTP ---> MAP kinase,
PI3 kinases ----->AKT kinases,
PLCgammaPIP2 ---->IP3 + DAG
46
PI3 -->AKT kinases are involved in
cell survival (inhibition of apoptosis),
proliferation,
insulin signaling
47
PLC --> IP2 +DAG
IP2 -->IP3 causes inc Ca ,
| DAG --> activates PKC (Ca also activates PKC)
48
how does RAS-GTP get activated
tyrosine kinase phosphorylation -->GRB2
--->SOS ---->RasGDP ---->Ras GTP;
adaptor proteins and linker proteins lead to RAS (an oncogene) and binding to ATP makes it active
49
How does RAS-GTP get shup off
intrinsic GTPase activity cleaves terminal phsophate
50
Down stream signal from Ras-GTP
Raf --> MEK --> ERK --> nucleus -->
| activation of transcription cFOS, cMYC, cJUN
51
cFOS, cMYC, cJUN are
competence factors and when they are active they allow the cell to get out of G1 and start dividing
52
Receptors without kinase activity
recurit JAK (janus kinase) for downstream signaling via STAT (signal transducers and activators of transcription ) sending signal to the nucleus
53
G Protein Linked receptors
adenyl cyclase - inc cAMP to activate cAMP dependent kinases.
PLC gamma - activates PKC and increases Ca2+
54
Signal transduction occurs via
MAP kinase,
PI3 kinase, IP3 signaling/PKC,
cyclicAMP kinases,
JAK/STAT pathway
55
Transcription factors have
DNA binding zinc fingers
56
TFs will
increase or decrease transcriptin
57
TF phosphorylation will
alter activity
58
TFs can be
protooncogenes/tumor supressor genes (myc, fos, p53)
59
Growth in serum
occurs bc you have coagulation and activated plateltes will secrete a lot of growth factors
60
Growth in plasma
does not occur bc of lack of activate plateltes that secrete growth factors
61
plasma and PDGF or PDGF and EGF will result in
growith bc cells need at least 2 signals, one to get comptence factors activated and another to push the cycle forward
62
Cyclin dependent kinases are
constitutive and are inactive until the appropriate cyclin is produced and then they phosphorylate different proteins
63
cylin in G1-->S
Cyclin E
64
Cyclin in S-->G2
Cyclin A
65
Cyclin in G2-->M
cyclin B
66
CDK + cyclin -->
CDK (active)
67
CDK active -->
posphorylation of numerous proteins
68
cyclins are degraded by
ubiquitine/proteosome complex
69
liver lobes
are not perfectly separated so if we cut off one we wont regenerate the full part we cut off
70
Kupfer cells and endothelial cells of sinusoids in liver make
TNF and IL6
71
insuline and norepinephrine are
adjuvants in the cell cycle making it more robust to get to S phase
72
G0 --> G1
Liver NPCs,
TNF,
IL6,
cFOS, cJUN, cMYC-->AP1-->NFkB,Stat3
73
G1-->S
```
HGF,
TGFalpha,
Insulin,
NE,
Bcl-X
```
74
S --> M
cyclins,
CDK4,
CDK2
75
TGFbeta and activin
inhibition of cell cycle/ epithelial growth
76
Extracellular matirx is made of
collagens (1-9),
elastin/fibrilin,
glycoproteins ,
proteoglycans
77
glycoproteins in ECM
fibronectin,
laminin,
integrins
78
Proteoglycans in ECM
heparan and chondroitin sulfate,
| hyaluronic acid
79
ECM is a
skeleton,
intracellular glue,
potent signaling pathway
80
ECM has
interstitial matirx,
basement membrane, and
provisional matrix
81
ECM interstitial matrix
fibrillar and nonfibrillar collagen,
elastin, and
varying amounts of other constituents
82
ECM Basement membranes
epithelial cell contact,
amorphous nonfibrillar collagen (4),
laminin, and
others
83
ECM provisional matrix
temporary accumulation of ECM at sites of injury
84
what is the most abundant animal protein
collagen
85
collagen structure
triple helix of 3 alpha chains
86
collagen synthesis
chains undergo hydroxylation reactions that need VitC.
87
Collagen modification post secretion
cleavage and crosslinking
88
types of collagen
27 types encoded by 41 genes over 14 chromosomes - huge genetic target
89
no Vit C
you don't heal bc no collagen syn
90
full steps of collagen syn
```
alpha chain syn off ribosome,
hydroxylation,
glycosilation,
alphachain arrangement inot tripple helix,
clipping of N and C term peptides,
crosslinking
```
91
why the crosslinking?
makes it stiffer
92
type 1 collagen
high tensile strength
93
type 1 collagen is found in
skin, bone, tendons, most organs
94
type 2 collagen
thin fibrils, sturctural protein
95
type 2 collagen is found in
cartilage, vitreous humor
96
type 3 collagen
thin pliable
97
type 3 collagen is found in
blood vessels, uterus, skin
98
type 4-6 collagen
amorphous
99
type 4-6 collagen is found in
basement membrane and interstitial tissues
100
type 7
anchoring filament
101
type 7 found in
dermal-epidermal junction
102
type 8
endothelium-descement membrane
103
type 9
cartilage
104
Elastin is found in
vessels, skin, uterus, lung
105
Elastin can
stretch then snap back
106
Elastin sturcture
central core protein (elastin) surounded by fibrilin
107
Elastin elasticity controlled by
crosslinking
108
Most insoluble and resistant to break down protein
elastin
109
In arterial walls elastin is
slowly replaced
110
Adhesive glycoproteins
bind ECM and to cell receptors - like glue
111
adhesive glycoprotein examples
fibronectin and laminin
112
fibronectin is found in
many locations and serum -helps cells bind and grow better
113
laminin is found in
basement membranes
114
Fibronectin size
very large 450 kDa secreted by many cell types like the liver
115
fibronectin binds
many cells especially endothelial cells, via a receptor that recognizes the tripeptide sequence
RGD (argenin,glycine,aspartat)
116
fibronectin directly mediates
attachment spreading and migration of cells and modifies responses to growth factors
117
RGD motif on fibrin binds
integrins on endothelial cells
118
fibrin has binding domains for
heparan,
fibrin,
collagen and
integrins
119
laminin size
very large 820kDa
120
what is the most abundant glycoprotein in the basement membrane
laminin
121
laminin spanns the basement membrane and binds
integrins on cells
122
laminin binds
collagen 4 and heparan sulphate in basement membrane
123
laminin mediates
spreading,
adhesion,
alignment, and
responses to growthfactors
124
if you destroy laminin
you lay down type 1 collagen instead of type 4 and you scar. You'll fill the hole but won't resolve.
125
cell adhesion proteins/molecules
immunoglobulin family,
cadherins,
integrins,
selectins
126
Ig family CAMs
same or different cell type interactions
127
Caderhin CAMs
Ca dependent same cell interactions (like btw columnar cells for ex)
128
Integrin CAMs
very broad range of binding cell-cell and cell-ECM
129
Selectin CAMs
C-type lectin involved in leukocyte endothelial binding
130
Cadherins occur at
zona adherins and desmosomes
131
Cadherin linkage with
cytoskeleton through alpha and beta catenin
132
cadherins modulate
proliferation,
differentiation, and
motility (contact inhibition of replication)
133
beta catenin is an important inducer of
colon carcinoma
134
if cadherins are taken away
loss of contact inhibition resulting in neoplasia
135
Integrins
cell receptors that bind to adhesive proteins (ex RGD seq of fibronectin)
136
Integrins are linked to
cytoskeleton and signal transduction pathways
137
alpha integrins
14 subtypes
138
beta integrin chain
8 subtypes
139
integrin chain chain
alpha and beta
140
integrins are found on
many cells
141
integrins mediate
leukocyte adhesion,
platelet aggregation,
wound healing
142
some cells undergo apoptosis if
thye are not bound to the matrix by integrins
143
Matricellular protein examples
SPARC,
Thrombospondins,
Osteopontin,
Tenacin
144
Matricellular Proteins
nonstructural components of ECM but modify cell-ECM interactions
145
Matricellular Protein - SPARC
secreted protein acidic and rich in cystien aka osteonectin
146
SPARC is involved in
tissue remodling,
inhibits angiogenesis,
(Ca++?)
147
Thrombospondins
inhibit angiogenesis
148
Osteopontin
Ca2+,
| leukocyte migration
149
Tenacin
cell morphogenesis and
| cell adhesion
150
Proteoglycans
protein linked to polysaccharides containing a sulfate -
| along with hyaluronana are the 3rd general sturctural component of ECM
151
Proteoglycan examples
heparn sulfate,
chondroitin sulfate,
dermatan sulfate
152
proteoglycans are named by
the repeating disaccharide
153
proteoglycans can also be
cell membrane proteins like Syndecan
154
Syndecan
spans membrane and binds GFs and ECM and interacts with actin
155
Hyaluronan is made of
simple end to end disaccharide repeats
156
hyaluronan binds to
many receptors including CD44 that mediates migration and proliferation
157
unique feature of hyaluronan is that it binds
massive amouns of H2O thus excellent cushion effect so found in joints
158
hyaluronan inhibits
cell-cell adhesion and facilitates cell migration
159
heparan sulfate binds
FGF that finds the FGF receptor
160
the same growth factors and cells in varied ECM will
vary the response
