Week 3: Signal transduction II, RECEPTOR TYROSINE KINASES Flashcards
T/F: This was the worst lecture that’s been given in UMD’s 30 year history
True
What does BCR-ABL signaling mimic?
growth factor activation
What does a mutation in the BCR-ABL pathway cause?
CML
Where in the vicinity of the cell is the tyrosine kinase domain located and what is it bound to?
found intracellularly, bound to a ligand binding domain
When do receptors typically signal intracellularly?
When they dimerize and are activated by a ligand, but heterodimers with various partners are common
What do SH2 domains do?
recognize phospho-tyrosine and connect the RTK phosphorylation events to various “second messengers”
How does the signal manifest in terms of cell biology?
modulation of transcription factors
What does HIF-alpha sense? What does it do?
low oxygen state; translocates to nucleus and induces hypoxia-inducible genes (VEGF and PDGF)
What helps to degrade HIF protein?
Prolyl hydroxylase, vitamin C, alpha-ketoglutarate, O2 via E3 ligase activity
How do you block VEGF signaling?
Antibodies to it’s receptor, TKIs to block intracellular signaling (inhibition of tyrosine kinase), rapalogues to block Akt/mTOR pathway
What are some drugs that are FDA approved to inhibit VEGF-axis?
sorafenib, sunitinib, IFN/bevacizumab, pazaopanib, axitinib
What are side effects of VEGFR inhibitors?
cause hypertension, hypothyroidism, loss of hair pigmentation, can cause GI perforation, paricardial effusion, myelosuppression, hepatic toxicity
What is unique about HER2?
doesn’t contain a binding domain, helps drive proliferation when it dimerizes with EGFR
What is trastuzumab used to treat?
antibody to the extracellular domain of Her2 protein
What is lapatinib? What does it do?
TKI against HER2, blocks both the EGFR and Her-2
