Signaling #11

Question 1

What is the critical role of dimerization in RTK activation?

Answer 1

Dimerization is critical for activation of RTKs.

Question 2

What type of protein is Ras?

Answer 2

Ras is a small G-protein (monomeric 21-kD).

Question 3

What regulates the switching of Ras between active and inactive states?

Answer 3

Ras is regulated by guanine nucleotide exchange factor (GEF) and GTPase activating proteins (GAPs).

Question 4

True or False: Mutant Ras proteins can dissociate GTP.

Answer 4

False

Question 5

What percentage of human cancers have ras gene mutations?

Answer 5

30%

Question 6

What happens to Ras when there are mutations in Ras-GAPs?

Answer 6

Ras remains activated longer than it should.

Question 7

What state is the G protein in when bound to GDP?

Answer 7

Inactive

Question 8

What facilitates the rapid switching of Ras to its active state?

Answer 8

Guanine nucleotide exchange factors (GEFs).

Question 9

Which protein is the GEF in the RTK MAPK pathway?

Answer 9

SOS

Question 10

What are the components of Grb-2?

Answer 10

Grb-2 is composed of SH2 and SH3 domains.

Question 11

What does the SH2 domain of Grb-2 bind to?

Answer 11

Specific phosphotyrosines on activated RTK.

Question 12

What is the function of the SH3 domains of Grb-2?

Answer 12

Bind to proline-rich regions of SOS.

Question 13

How does Ras get activated after RTK dimerization?

Answer 13

An adapter protein (Grb-2) and a GEF (SOS) link activated RTKs to Ras.

Question 14

What is the role of the phosphatase PP2A in Raf activation?

Answer 14

Dephosphorylates serine residues on Raf to enable its activation.

Question 15

What is Raf also known as?

Answer 15

MAPKKK

Question 16

What is the only target substrate of MEK?

Answer 16

MAPK

Question 17

What type of kinase is MAPKK (MEK)?

Answer 17

Dual specificity kinase.

Question 18

What must occur for MAPK to become fully active?

Answer 18

Phosphorylation on both threonine and tyrosine.

Question 19

What transcription factors does activated MAPK modify?

Answer 19

TCF and SRF.

Question 20

What does MAPK phosphorylate that increases transcriptional frequency?

Answer 20

The kinase p90Rsk.

Question 21

What is the serum response element (SRE)?

Answer 21

An enhancer element regulating cFos and other target gene transcriptional events.

Question 22

Fill in the blank: Ras cycles between active and _______ forms.

Answer 22

inactive

Question 23

What role does the 14-3-3 protein play in Raf activation?

Answer 23

It holds Raf in an inactive state by binding to a phosphoserine.

Question 24

What is the effect of Ras forming nanoclusters?

Answer 24

Promotes Raf dimerization.

Question 25

What happens to Raf when it interacts with Ras-GTP?

Answer 25

Destabilizes the interaction of Raf with 14-3-3, allowing for activation.

Question 26

What is the main consequence of MAPK activation?

Answer 26

Induces transcription of c-fos.

Question 27

What does MAPK phosphorylate?

Answer 27

TCF ## Footnote MAPK phosphorylation occurs in a similar fashion across different pathways.

Question 28

What is the function of the SRE?

Answer 28

It is an enhancer element regulating cFos and other target gene transcriptional events.

Question 29

Which genes are regulated by the RTK/Ras pathway?

Answer 29

Early response genes such as c-fos.

Question 30

What allows for activated transcription following growth factor stimulation?

Answer 30

Serum response elements.

Question 31

What is c-fos?

Answer 31

An early response gene/transcription factor required for the induction of delayed response genes including cyclin D.

Question 32

How is RTK signaling downregulated?

Answer 32

By protein phosphatases, activated MAPK/ERK1/2, endocytosis, and RTK ubiquitination.

Question 33

What is Her2/neu/ErbB-2?

Answer 33

A Receptor Tyrosine Kinase of the epidermal growth factor class that stimulates proliferation.

Question 34

What can mutations in the transmembrane region of Her2/neu cause?

Answer 34

Constitutive dimerization in an activated state.

Question 35

What is associated with poor survival in breast cancer patients?

Answer 35

Amplification or overexpression of Her-2.

Question 36

What type of therapy is Herceptin?

Answer 36

A humanized monoclonal antibody targeting Her-2.

Question 37

What mechanism does Herceptin use to alert the immune system?

Answer 37

CD16-mediated antibody-dependent cellular cytotoxicity.

Question 38

What percentage of human tumors have a Ras mutation?

Answer 38

30%.

Question 39

Which cancers are associated with Ras mutations?

Answer 39

Pancreatic, colon, lung, thyroid, bladder, ovarian, breast, skin, liver, kidney, and some leukemias.

Question 40

What is the target of farnesyl transferase inhibitors?

Answer 40

To block Ras localization to the inner membrane.

Question 41

What is progeria?

Answer 41

A progressive genetic disorder causing rapid aging in children.

Question 42

What is the average life expectancy for a child with progeria?

Answer 42

About 13 years.

Question 43

What does Lonafarnib do in the treatment of progeria?

Answer 43

Blocks farnesylation of progerin.

Question 44

What is the role of farnesyl transferase in Ras signaling?

Answer 44

It is responsible for the attachment of a farnesyl isoprenoid, critical for Ras localization.

Question 45

What is the effect of binding a small molecule to the RAS-binding domain of RAF?

Answer 45

It prevents functional association with RAS and impairs tumorigenic proliferation.

Question 46

What is one strategy to block MAPK signaling?

Answer 46

Prevent Raf/Ras interactions.