FOM 7.2.3 Flashcards
What is the basic structure of a growth factor receptor?
Extracellular binding domain, transmembrane region and intracellular domain that has tyrosine kinase activity
Upon binding the ligand what is next immediate step for the growth factor receptor?
dimerization
Dimerization of the receptor leads to what?
Cross phosphorylation which creates binding sites for Grb2 and SOS
Why does the Grb2 bind to the phosphate?
The Grb2 has a domain that is positive that allows the negative phosphate group to fit right in it
Grb2 has binding sites for what?
The phosphorylated receptor and SOS
What is SOS?
Guanine Nucleotide exchange factor that will activate RAS protein
What does RAS then do after activation?
It will activate RAF which will activate MEK which will activate ERK which will activate TFs. This is known as a MAPK cascade.
What is the difference in structures between the cytokine receptors and the growth factor receptors?
The cytokine receptors do not posses intrinsic tyrosine kinase activity and they associate with JAK proteins
After binding the cytokine to the receptor what happens?
Dimerization leads to conformational change and JAK protein phosphorylation.
JAK protein phosphorylation leads to what?
It leads to receptor phosphorylation, the receptor can then bind to STAT proteins.
Binding of STAT proteins to the receptor leads to what?
Phosphorylation of the STAT proteins, their subsequent dimerization and translocation into the nucleus
What is the role of iNOS signaling in the JAK/STAT pathway?
Secretion of interferon leads to JAK/STAT signaling and up-regulation of iNOS protein which creates nitric oxide and kills the threat
What is the pathway of growth factor activation?
Binding of the ligand induces a receptor dimerization. The dimerization then leads to cross-phosphorylation. This provides a docking point for Grb2 which is bound to SOS. SOS then activates Ras which activates Raf. Subsequent MAPK cascade leads to transcription activation that mediates differentiation and proliferation
What is the pathway of cytokine activation?
Binding of the cytokine leads to dimerization and activation of JAK proteins. The JAK proteins then phosphorylate the receptor which bind to STAT proteins. The STAT proteins are phosphorylated which leads to a dimerization that translocates the proteins to the nucleus to affect transcription.
What is the role of phosphatases?
These dephosphorylate receptors, MAP Kinases and TFs
What is the role of GAPs?
These are GTPase activating proteins. THese increase intrinsic GTPase activity of RAS leading to hydrolysis of GTP to GDP and turning it off
How are receptors inactivated?
They are internalized and degraded or recycled to the cell surface
What is the role of PIAS?
These are protein inhibitors of STATs that bind to phosphorylated receptors and keep them from affecting transcription
What is the role of SOCS?
These bind to JAK proteins and keep STATs from binding
These are also though to have the ubiquitin domain that degrades JAK
What is wrong in inflammatory bowel disease?
Increased activation of STAT proteins and over expression of interferon
What is wrong in myleoproliferative disorders?
Mutation in JAK leading to signaling in the absence of cytokines
What is wrong in achondroplasia?
It is a result of abnormal FGF receptor activation. Activation in the absence of FGF leads to premature expression of p21 and premature arrest of bone formation.
What is the importance of oncogenes?
These maintain cell cycle and regulate proliferation. Mutations can lead to uncontrollable cell growth
A mutation in RAS that keeps it with GTP can lead to what?
Constant activity of MAPK cascade which will drive cellular proliferation and promote tumor growth
Over expression of ErbB2 can lead to what?
lead to increased tyrosine kinase activity and increased cell proliferation
What is the difference between the normal BRAF and the V600E mutation?
The V600E mutation subs a carboxylic acid sidechain. This mean the protein keeps the negative charge and it is active. The normal protein binds phosphate groups that can be removed.
What is interesting about PLX?
It works on melanoma V600E mutations but not colon cancer mutations
