Lecture 24 - Cancer Genetics 2 (Signaling Pathways and Intervention)

Question 1

Which is NOT a function of SH2 domain containing proteins?

A. Recruit SH2 proteins to the plasma membrane
B. Provide docking sites for association with other proteins
C. Bind proline rich sequences of 9 or 10 residues
D. Promote phosphorylation of associated proteins
E. Stimulate enzyme activity of associated proteins

Answer 1

C. SH3 domains are a second motif of SOME proteins that dock to activated RTKs, and these bind proline rich sequences.

Question 2

___________ are the largest family of enzyme linked receptors.

Answer 2

Receptor tyrosine kinases

Question 3

The most common amino acids phosphorylated by protein kinases are ______ and ______.

Answer 3

1. serine
2. threonine

*Note: phosphorylation of tyrosine occurs less frequently

Question 4

The structure of tyrosine kinase receptors has 3 major parts. What is the function of the N-terminal?

Answer 4

Extracellular ligand binding domain

Question 5

The structure of tyrosine kinase receptors has 3 major parts. What is the function of the C-terminal domain?

Answer 5

Cytosolic; protein tyrosine kinase activity

Question 6

The structure of tyrosine kinase receptors has 3 major parts. What are they?

Answer 6

1. N-terminal (extracellular ligand binding domain)
2. Single ‘transmembrane’ domain
3. C-terminal (cytosolic site of protein TK activity)

Question 7

Most receptors are ____(a)____ but some receptors, such as ___(b)___ are dimers consisting of two polypeptide chains.

Answer 7

a) monomeric

b) insulin

Question 8

The process in which a ligand binds to the extracellular domain of the RTK and cross-links the receptor is called:

Answer 8

dimerization

Question 9

The 2 main types of ligand induced dimerization are:

Answer 9

1. auto-phosphorylation

2. cross phosphorylation

Question 10

Ligand induced dimerization serves to: (2 functions)

Answer 10

1. increase receptor kinase activity

2. create binding sites for specific proteins that transduce the intracellular signal

Question 11

_____(a)_____ are binding sites for a unique set of intracellular proteins that utilize select domains called ____(b)_____.

Answer 11

a) Phosphotyrosine sites

b) SH2 domains

Question 12

What protein generates diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3)?

Answer 12

Phospholipase C-gamma

Question 13

Which product generated by phospholipase C-gamma (PLC-gamma) functions to activate serine/threonine protein kinases?

Answer 13

DAG

Question 14

Which product generated by phospholipase C-gamma (PLC-gamma) binds to ligand-gated Ca2+ channel receptors triggering release of intracellular stores of Ca2+ from the ER?

Answer 14

IP3

Question 15

The ________ pathway activates RTKs by mobilizing a family of serine/threonine protein kinases.

Answer 15

MAPK

Question 16

The founding member of the MAPK family is the _______.

Answer 16

extracellular signal regulated protein kinase 1/2 (ERK-1/2)

Question 17

The Ras proteins belong to the large super family of:

Answer 17

monomeric GTPases

Question 18

The Ras proteins contain a covalently attached prenyl group that helps to perform what function?

Answer 18

Anchor the protein in the membrane

Question 19

The Ras protein cycles from __(a)__ to __(b)__.

Answer 19

a) GDP bound inactive form

b) GTP bound active form

Question 20

What are the two classes of signaling proteins that regulate Ras activity?

Answer 20

1. GAPs (GTPase-activity proteins)

2. GEFs (guanine nucleotide exchange factors)

Question 21

What is the function of GEF signaling proteins?

Answer 21

Activate Ras - promote exchange of bound nucleotide by stimulating loss of GDP.

Question 22

______ increase the rate of hydrolysis of bound GTP by Ras, thereby inactivating it.

Answer 22

GAP signaling proteins

Question 23

Which of the following is FALSE regarding non-receptor tyrosine kinases?

A. They are receptors for growth factor signaling
B. They are associated with receptors
C. They phosphorylate target proteins
D. All of the above are TRUE.

Answer 23

A. Non-receptor tyrosine kinases are NOT receptors for growth factor signaling.

Question 24

_______ receptors act by stimulating intracellular non-receptor tyrosine kinase pathways.

Answer 24

Cytokine

Question 25

Alterations in cytokine receptors can cause _________ disease.

Answer 25

Autoimmune

Question 26

Like RTKs, cytokine receptors contain extracellular ligand binding domains, transmembrane domains, and cytosolic domains.

However, the intracellular domains of cytokine receptors lack _________.

Answer 26

intrinsic enzyme activity

Question 27

The ________ pathway provides a direct link between receptor stimulation and transcriptional activation.

Answer 27

JAK/STAT pathway

Question 28

What are STAT proteins?

Answer 28

transcription factors that contain SH2 domains

Question 29

How do STAT proteins appear in unstimulated cells?

Answer 29

Localized in cytoplasm in an inactive state

Question 30

When cytokine receptors are stimulated, how do STAT proteins appear?

Answer 30

STAT proteins bind via their SH2 domains to specific phosphotyrosine residues on receptors

Question 31

After tyrosine-phosphorylated STAT proteins dimerize, where do they translocate?

Answer 31

The nucleus - to stimulate transcription of target genes

Question 32

The ____________ receptors function to reverse the effect of protein tyrosine kinases by removing phosphates from phosphotyrosine residues.

Answer 32

protein tyrosine phosphatase receptors

Question 33

Endocytosis of ligand-receptor complexes is another mechanism to perform what function?

Answer 33

Terminate receptor activation - leading to their internalization or degradation.

Question 34

What are ‘Human Epidermal Growth Factor Receptors’ (HERs)?

Answer 34

Receptors for the EGF (epidermal growth factor) family of ligands.

*Note: these receptors are members of the RTK family

Question 35

________ between ErbB3 and other ErbB proteins are required for normal development.

Answer 35

Heterodimers

Question 36

What are 4 primary traits that determine the diversity of EGF ligand responses?

Answer 36

1. receptor can bind multiple ligands
2. ligand can bind multiple receptors
3. dimerization between two identical subunits
4. recruitment of various signaling molecules

Question 37

Mutations in _____ receptors that lead to over-expression or constitutive activation are found in many human cancers.

Answer 37

ErbB

Question 38

Why do ErbB receptor mutations contribute to tumorigenesis?

Answer 38

They enhance the cell’s response to growth factors, leading to aberrant and enhanced cellular proliferation.

Question 39

One therapeutic approach in breast cancer has been to generate monoclonal antibodies, such as the recent FDA-approved antibody against HER2. What receptor domain does this approach target?

Answer 39

extracellular domains of ErbB receptors

Question 40

Antibodies that bind the extracellular domain of growth factor receptors serve what 2 primary functions?

Answer 40

1. block growth factor-receptor interaction

2. induce immune responses that cause cell lysis and cell death

Question 41

_________ act by competing for the ATP binding site and thereby block RTK activation.

Answer 41

ATP analogues

Question 42

Immunotoxins contain __________ toxins fused to growth factors to ultimately trigger cell death.

Answer 42

growth factors

Question 43

__________ is a monoclonal antibody directed against ErbB1.

Answer 43

Cetuximab (Erbitux)

Question 44

_____ is an ErBB1 tyrosine kinase inhibitor.

Answer 44

Gefitinib (Iressa)

Question 45

_______ is an antibody against HER2 used in treatment of overexpressing HER2 breast cancer.

Answer 45

trastuzumab (Herceptin)

Question 46

What is gleevac?

Answer 46

An ATP analogue that acts by competing for the ATP binding site for some non-receptor tyrosine kinases.

Question 47

The following event is triggered by the auto- and cross-phosphorylation of a tyrosine kinase receptor, such as the platelet-derived growth factor receptor:

A. Ligand binding
B. Antagonist binding
C. Nuclear transport
D. Docking of proteins containing an SH3 domain

Answer 47

D. These function to create bind sites for proteins that enhance a specific intracellular signal (such as SH3).

Question 48

An “activating” mutation within the Ras protein could have the following consequences:

A. Decreased hydrolysis of Ras-bound GTP
B. Decreased binding to a Ras guanosine nucleotide exchange protein
C. Increased association of Ras with the Grb-2 adaptor protein.
D. Increased phosphorylation of Ras-bound GDP to GTP.

Answer 48

A. Hydrolysis of Ras-bound GTP inactivates Ras.

Question 49

Cytosine arabinoside (araC) is used as an effective chemotherapeutic agent for cancer, although resistance to this drug may eventually develop. In certain cases, resistance is related to an increase in the enzyme cytidine deaminase in the tumor cells. This enzyme would produce:

A. Cytosine
B. Hypoxanthine
C. Xanthine
D. Uracil

Answer 49

D.