Unit 2- Growth Factors, Receptors, and Cancer Flashcards
(41 cards)
What are growth factors?
- signaling proteins that stimulate cell growth/ differentiation/ survival
Why do we need growth factors?
- cell communication
- to maintain proper tissue architecture
- many cell types > control proliferation, so have the right # of cells
Why do we need growth factor receptors?
- plasma membrane is impermeable to most signaling molecules (h20 soluble)
- proteins/ genes that regulate cell function are located within cell
- receptors transmit extracellular signals > intracellular proteins
How can growth factors contribute to cancer?
- GF/ GFR signaling is tightly controlled
- tumor cells can alter GF production/ GFR signaling
What gene provided the initial clues about cell signaling via growth factors?
Src (v-src = viral src)
- first discovered oncoprotein
- gene from rous sarcoma virus > induced sarcomas in chickens
What happened when cells transformed with v-src?
- ↑ cell proliferation
- altered glucose uptake/ cell shape
- resulted in anchorage-independent growth > tumor formation
What kind of a protein is Src/ how was this determined?
Tyrosine Kinase
- anti-Src antibody phosphorylated
Why is Src unlike other kinases?
- phosphotyrosine rare compared to phosphothreonine/ phosphoserine
- many substrates (>50) can explain pleiotropic effects
What is the common structure of tyrosine kinase receptors?
- at least 1 tyrosine kinase domain in intracellular space
- ligands bind extracellular
- most receptors are monomers/ dimerize when bind ligand
What are gene mutations?
- permanent alteration in DNA sequence that makes up a gene, so sequence differs from what is found in most people
How can mutations impact the function of a protein?
- affect whether full-length/ truncated protein is produced (↑/↓ function)
- influence intracellular localization
- impact whether protein expressed in particular cell
- alter ability of signals to turn on/off protein
- alter protein ability to interact with other cell components
How can mutations lead to deregulation of receptor signaling?
normal receptor > ligand binds > ligand-dependent firing
mutations > ligand-independent firing
What are 3 mechanisms of deregulation of receptor signaling in tumors?
mutation > ligand-independent firing
autocrine signaling
receptor amplification > ↑ # of receptors to ↑ activation
How are tyrosine kinase receptors activated?
Transphosphorylation
> monomers dimerize
What are the Src homology domains? (protein interaction domains)
SH2- allows protein to bind phosphorylated tyrosine residue
SH3- allows protein-protein interactions
What provides protein binding sites?
- receptor phosphorylation
What provides negative feedback of tyrosine kinase signaling?
Phosphatases- remove phosphate from tyrosine
(Kinase-add phosphate/ activate)
What factors promote Ras activation/ inactivation?
GDP-Ras = inactive/ GTP-Ras = active
GEF = Guanine Exchange Factors > promote Ras activation ex) Sos
- Shc/ Grb2 proteins recruit Sos
GAP = GTPase Activating Protein > GTP hydrolysis/ Ras inactivation
How does Ras signaling work?
Ras- tethered/ stuck on plasma membrane
Ras = GTPase (GDP-Ras = inactive/ GTP-Ras = active)
- SOS (a GEF) recruited to Ras > facilitates GDP > GTP exchange > Ras activation
How can a mutation impact Ras signaling?
- oncogenic mutation causes GAP (GTPase activating protein) blockage
> GAP can not inactivate Ras (GTP-Ras overactivated)
What are the major Ras signaling cascades?
MAPK > ↑ transcription factors
Ral > metastasis
AKT/PKB > promotes cell proliferation/ survival/ growth
How does Ras > AKT/PKB signaling work?
PIP2 = phospholipid inactive/ PIP3 = active
- Ras activates PI3K enzyme > PIP2 to PIP3 > AKT/PKB localization to plasma membrane > activation
- PTEN inactivates PIP3 to PIP2 (opposite of PI3K)
What is the result of a loss of PTEN in AKT/ PKB signaling?
- AKT hyperactivation
- PTEN normally inactivates PIP3 > PIP2/ controls AKT/ PKB activation
What does AKT/PKB signaling do?
- stimulates proliferation
- stimulates angiogenesis
- inhibits apoptosis
