FOM 7.2.3

Question 1

What is the basic structure of a growth factor receptor?

Answer 1

Extracellular binding domain, transmembrane region and intracellular domain that has tyrosine kinase activity

Question 2

Upon binding the ligand what is next immediate step for the growth factor receptor?

Answer 2

dimerization

Question 3

Dimerization of the receptor leads to what?

Answer 3

Cross phosphorylation which creates binding sites for Grb2 and SOS

Question 4

Why does the Grb2 bind to the phosphate?

Answer 4

The Grb2 has a domain that is positive that allows the negative phosphate group to fit right in it

Question 5

Grb2 has binding sites for what?

Answer 5

The phosphorylated receptor and SOS

Question 6

What is SOS?

Answer 6

Guanine Nucleotide exchange factor that will activate RAS protein

Question 7

What does RAS then do after activation?

Answer 7

It will activate RAF which will activate MEK which will activate ERK which will activate TFs. This is known as a MAPK cascade.

Question 8

What is the difference in structures between the cytokine receptors and the growth factor receptors?

Answer 8

The cytokine receptors do not posses intrinsic tyrosine kinase activity and they associate with JAK proteins

Question 9

After binding the cytokine to the receptor what happens?

Answer 9

Dimerization leads to conformational change and JAK protein phosphorylation.

Question 10

JAK protein phosphorylation leads to what?

Answer 10

It leads to receptor phosphorylation, the receptor can then bind to STAT proteins.

Question 11

Binding of STAT proteins to the receptor leads to what?

Answer 11

Phosphorylation of the STAT proteins, their subsequent dimerization and translocation into the nucleus

Question 12

What is the role of iNOS signaling in the JAK/STAT pathway?

Answer 12

Secretion of interferon leads to JAK/STAT signaling and up-regulation of iNOS protein which creates nitric oxide and kills the threat

Question 13

What is the pathway of growth factor activation?

Answer 13

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

Question 14

What is the pathway of cytokine activation?

Answer 14

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.

Question 15

What is the role of phosphatases?

Answer 15

These dephosphorylate receptors, MAP Kinases and TFs

Question 16

What is the role of GAPs?

Answer 16

These are GTPase activating proteins. THese increase intrinsic GTPase activity of RAS leading to hydrolysis of GTP to GDP and turning it off

Question 17

How are receptors inactivated?

Answer 17

They are internalized and degraded or recycled to the cell surface

Question 18

What is the role of PIAS?

Answer 18

These are protein inhibitors of STATs that bind to phosphorylated receptors and keep them from affecting transcription

Question 19

What is the role of SOCS?

Answer 19

These bind to JAK proteins and keep STATs from binding

These are also though to have the ubiquitin domain that degrades JAK

Question 20

What is wrong in inflammatory bowel disease?

Answer 20

Increased activation of STAT proteins and over expression of interferon

Question 21

What is wrong in myleoproliferative disorders?

Answer 21

Mutation in JAK leading to signaling in the absence of cytokines

Question 22

What is wrong in achondroplasia?

Answer 22

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.

Question 23

What is the importance of oncogenes?

Answer 23

These maintain cell cycle and regulate proliferation. Mutations can lead to uncontrollable cell growth

Question 24

A mutation in RAS that keeps it with GTP can lead to what?

Answer 24

Constant activity of MAPK cascade which will drive cellular proliferation and promote tumor growth

Question 25

Over expression of ErbB2 can lead to what?

Answer 25

lead to increased tyrosine kinase activity and increased cell proliferation

Question 26

What is the difference between the normal BRAF and the V600E mutation?

Answer 26

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.

Question 27

What is interesting about PLX?

Answer 27

It works on melanoma V600E mutations but not colon cancer mutations