Signaling #11 Flashcards
What is the critical role of dimerization in RTK activation?
Dimerization is critical for activation of RTKs.
What type of protein is Ras?
Ras is a small G-protein (monomeric 21-kD).
What regulates the switching of Ras between active and inactive states?
Ras is regulated by guanine nucleotide exchange factor (GEF) and GTPase activating proteins (GAPs).
True or False: Mutant Ras proteins can dissociate GTP.
False
What percentage of human cancers have ras gene mutations?
30%
What happens to Ras when there are mutations in Ras-GAPs?
Ras remains activated longer than it should.
What state is the G protein in when bound to GDP?
Inactive
What facilitates the rapid switching of Ras to its active state?
Guanine nucleotide exchange factors (GEFs).
Which protein is the GEF in the RTK MAPK pathway?
SOS
What are the components of Grb-2?
Grb-2 is composed of SH2 and SH3 domains.
What does the SH2 domain of Grb-2 bind to?
Specific phosphotyrosines on activated RTK.
What is the function of the SH3 domains of Grb-2?
Bind to proline-rich regions of SOS.
How does Ras get activated after RTK dimerization?
An adapter protein (Grb-2) and a GEF (SOS) link activated RTKs to Ras.
What is the role of the phosphatase PP2A in Raf activation?
Dephosphorylates serine residues on Raf to enable its activation.
What is Raf also known as?
MAPKKK
What is the only target substrate of MEK?
MAPK
What type of kinase is MAPKK (MEK)?
Dual specificity kinase.
What must occur for MAPK to become fully active?
Phosphorylation on both threonine and tyrosine.
What transcription factors does activated MAPK modify?
TCF and SRF.
What does MAPK phosphorylate that increases transcriptional frequency?
The kinase p90Rsk.
What is the serum response element (SRE)?
An enhancer element regulating cFos and other target gene transcriptional events.
Fill in the blank: Ras cycles between active and _______ forms.
inactive
What role does the 14-3-3 protein play in Raf activation?
It holds Raf in an inactive state by binding to a phosphoserine.
What is the effect of Ras forming nanoclusters?
Promotes Raf dimerization.
What happens to Raf when it interacts with Ras-GTP?
Destabilizes the interaction of Raf with 14-3-3, allowing for activation.
What is the main consequence of MAPK activation?
Induces transcription of c-fos.
What does MAPK phosphorylate?
TCF
MAPK phosphorylation occurs in a similar fashion across different pathways.
What is the function of the SRE?
It is an enhancer element regulating cFos and other target gene transcriptional events.
Which genes are regulated by the RTK/Ras pathway?
Early response genes such as c-fos.
What allows for activated transcription following growth factor stimulation?
Serum response elements.
What is c-fos?
An early response gene/transcription factor required for the induction of delayed response genes including cyclin D.
How is RTK signaling downregulated?
By protein phosphatases, activated MAPK/ERK1/2, endocytosis, and RTK ubiquitination.
What is Her2/neu/ErbB-2?
A Receptor Tyrosine Kinase of the epidermal growth factor class that stimulates proliferation.
What can mutations in the transmembrane region of Her2/neu cause?
Constitutive dimerization in an activated state.
What is associated with poor survival in breast cancer patients?
Amplification or overexpression of Her-2.
What type of therapy is Herceptin?
A humanized monoclonal antibody targeting Her-2.
What mechanism does Herceptin use to alert the immune system?
CD16-mediated antibody-dependent cellular cytotoxicity.
What percentage of human tumors have a Ras mutation?
30%.
Which cancers are associated with Ras mutations?
Pancreatic, colon, lung, thyroid, bladder, ovarian, breast, skin, liver, kidney, and some leukemias.
What is the target of farnesyl transferase inhibitors?
To block Ras localization to the inner membrane.
What is progeria?
A progressive genetic disorder causing rapid aging in children.
What is the average life expectancy for a child with progeria?
About 13 years.
What does Lonafarnib do in the treatment of progeria?
Blocks farnesylation of progerin.
What is the role of farnesyl transferase in Ras signaling?
It is responsible for the attachment of a farnesyl isoprenoid, critical for Ras localization.
What is the effect of binding a small molecule to the RAS-binding domain of RAF?
It prevents functional association with RAS and impairs tumorigenic proliferation.
What is one strategy to block MAPK signaling?
Prevent Raf/Ras interactions.
