Lecture 24 - Cancer Genetics 2 (Signaling Pathways and Intervention) Flashcards
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
C. SH3 domains are a second motif of SOME proteins that dock to activated RTKs, and these bind proline rich sequences.
___________ are the largest family of enzyme linked receptors.
Receptor tyrosine kinases
The most common amino acids phosphorylated by protein kinases are ______ and ______.
- serine
- threonine
*Note: phosphorylation of tyrosine occurs less frequently
The structure of tyrosine kinase receptors has 3 major parts. What is the function of the N-terminal?
Extracellular ligand binding domain
The structure of tyrosine kinase receptors has 3 major parts. What is the function of the C-terminal domain?
Cytosolic; protein tyrosine kinase activity
The structure of tyrosine kinase receptors has 3 major parts. What are they?
- N-terminal (extracellular ligand binding domain)
- Single ‘transmembrane’ domain
- C-terminal (cytosolic site of protein TK activity)
Most receptors are ____(a)____ but some receptors, such as ___(b)___ are dimers consisting of two polypeptide chains.
a) monomeric
b) insulin
The process in which a ligand binds to the extracellular domain of the RTK and cross-links the receptor is called:
dimerization
The 2 main types of ligand induced dimerization are:
- auto-phosphorylation
2. cross phosphorylation
Ligand induced dimerization serves to: (2 functions)
- increase receptor kinase activity
2. create binding sites for specific proteins that transduce the intracellular signal
_____(a)_____ are binding sites for a unique set of intracellular proteins that utilize select domains called ____(b)_____.
a) Phosphotyrosine sites
b) SH2 domains
What protein generates diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3)?
Phospholipase C-gamma
Which product generated by phospholipase C-gamma (PLC-gamma) functions to activate serine/threonine protein kinases?
DAG
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?
IP3
The ________ pathway activates RTKs by mobilizing a family of serine/threonine protein kinases.
MAPK
The founding member of the MAPK family is the _______.
extracellular signal regulated protein kinase 1/2 (ERK-1/2)
The Ras proteins belong to the large super family of:
monomeric GTPases
The Ras proteins contain a covalently attached prenyl group that helps to perform what function?
Anchor the protein in the membrane
The Ras protein cycles from __(a)__ to __(b)__.
a) GDP bound inactive form
b) GTP bound active form
What are the two classes of signaling proteins that regulate Ras activity?
- GAPs (GTPase-activity proteins)
2. GEFs (guanine nucleotide exchange factors)
What is the function of GEF signaling proteins?
Activate Ras - promote exchange of bound nucleotide by stimulating loss of GDP.
______ increase the rate of hydrolysis of bound GTP by Ras, thereby inactivating it.
GAP signaling proteins
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.
A. Non-receptor tyrosine kinases are NOT receptors for growth factor signaling.
_______ receptors act by stimulating intracellular non-receptor tyrosine kinase pathways.
Cytokine
Alterations in cytokine receptors can cause _________ disease.
Autoimmune
Like RTKs, cytokine receptors contain extracellular ligand binding domains, transmembrane domains, and cytosolic domains.
However, the intracellular domains of cytokine receptors lack _________.
intrinsic enzyme activity
The ________ pathway provides a direct link between receptor stimulation and transcriptional activation.
JAK/STAT pathway
What are STAT proteins?
transcription factors that contain SH2 domains
How do STAT proteins appear in unstimulated cells?
Localized in cytoplasm in an inactive state
When cytokine receptors are stimulated, how do STAT proteins appear?
STAT proteins bind via their SH2 domains to specific phosphotyrosine residues on receptors
After tyrosine-phosphorylated STAT proteins dimerize, where do they translocate?
The nucleus - to stimulate transcription of target genes
The ____________ receptors function to reverse the effect of protein tyrosine kinases by removing phosphates from phosphotyrosine residues.
protein tyrosine phosphatase receptors
Endocytosis of ligand-receptor complexes is another mechanism to perform what function?
Terminate receptor activation - leading to their internalization or degradation.
What are ‘Human Epidermal Growth Factor Receptors’ (HERs)?
Receptors for the EGF (epidermal growth factor) family of ligands.
*Note: these receptors are members of the RTK family
________ between ErbB3 and other ErbB proteins are required for normal development.
Heterodimers
What are 4 primary traits that determine the diversity of EGF ligand responses?
- receptor can bind multiple ligands
- ligand can bind multiple receptors
- dimerization between two identical subunits
- recruitment of various signaling molecules
Mutations in _____ receptors that lead to over-expression or constitutive activation are found in many human cancers.
ErbB
Why do ErbB receptor mutations contribute to tumorigenesis?
They enhance the cell’s response to growth factors, leading to aberrant and enhanced cellular proliferation.
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?
extracellular domains of ErbB receptors
Antibodies that bind the extracellular domain of growth factor receptors serve what 2 primary functions?
- block growth factor-receptor interaction
2. induce immune responses that cause cell lysis and cell death
_________ act by competing for the ATP binding site and thereby block RTK activation.
ATP analogues
Immunotoxins contain __________ toxins fused to growth factors to ultimately trigger cell death.
growth factors
__________ is a monoclonal antibody directed against ErbB1.
Cetuximab (Erbitux)
_____ is an ErBB1 tyrosine kinase inhibitor.
Gefitinib (Iressa)
_______ is an antibody against HER2 used in treatment of overexpressing HER2 breast cancer.
trastuzumab (Herceptin)
What is gleevac?
An ATP analogue that acts by competing for the ATP binding site for some non-receptor tyrosine kinases.
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
D. These function to create bind sites for proteins that enhance a specific intracellular signal (such as SH3).
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.
A. Hydrolysis of Ras-bound GTP inactivates Ras.
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
D.
