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CPPS 325 FINAL EXAM QUESTIONS AND VERIFIED
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What is the reciprocal of RTK? - CORRECT ANSWER- Receptor Tyrosine Phosphatases. They take the phosphate off the tyrosine residues to inactivate signalling cascades.
Ex. Transforming GF Beta superfamily of receptors, cell type dependent.
What is the major mechanism for receptor signal transduction? - CORRECT ANSWER- Tyrosine kinase phosphorylation
RTK vs. Serine/Threonine Phosphorylation? - CORRECT ANSWER- Tyrosine phosphorylation is rare (1%) relative to serine/threonine residue phosphorylation. Tyrosine phosphorylation is the major mechanism of receptor signal transduction.
What is the net effect of activated TKs? - CORRECT ANSWER- Tyrosine phosphorylation on target proteins.
What do TK pathways mediate? - CORRECT ANSWER- Cell growth (growth factors), differentiation, host defense, metabolic regulation, cell survival pathways (survival factors).
What are amplifiers of the TK pathways? - CORRECT ANSWER- PI3-K -> PIP
PLC -> DAG and InsP3&Ca2+
What are the 5 well-known enzyme-linked cell surface receptors? - CORRECT ANSWER- 1. Receptor Guanylyl Cyclase: produces cGMP
- RTK: phosphorylate tyrosine residues leading to association of signalling molecules and cascade
- TK Associated Receptors: associate with proteins having TK activity
- Receptor Tyrosine Phosphates: Removes phosphate on tyrosine residues
- Receptor Serine/Threonine Kinases: phosphorylate specific Serine/Threonine residues on IC signalling molecules
How are RTK and TK Associated Receptors different? - CORRECT ANSWER- RTK phosphorylate tyrosine while associated receptors bind/find proteins with TK activity to initiate the cascade of signalling.
What are RTK mediated actions in the cell? - CORRECT ANSWER- regulation of cell proliferation, differentiation, and cell motility, promotion of cell survival and modulation of cellular metabolism.
TKs exist in either the cytosol or as transmembrane receptors, what are the differences in the two types? - CORRECT ANSWER- Cytosol receptors have an src N-terminal region. Cytosol has no membrane spanning domain.
TM receptor has a single membrane spanning hydrophobic TM domain. Ex) Epidermal GF RTK.
What is src? - CORRECT ANSWER- Src is a non-receptor TK, so it does not span a membrane. It is a tyrosine kinase. And although it is cytoplasmic TK it can still bind to activated RTKs.
What is contact inhibition confluency? - CORRECT ANSWER- Stops Src domains signalling and therefore cells stop dividing.
Bind to phosphorylated tyrosine. Functional equivalent of the SH2 domain, except for the positional informational. Is not the C-terminus like SH2, but the N-terminus side of the phosphorylated tyrosine.
shc is a PTB protein.
What is the normal action that stops signalling for cell division in the src pathway? - CORRECT ANSWER- Contact Inhibition Confluency
How do PTB and SH2 domains differ? - CORRECT ANSWER- SH2 domains binds consensus on the C-terminus.
PTB domains binds the N-terminus.
They both mediate cellular signalling.
What is shc? - CORRECT ANSWER- PTB protein that docks at the N-terminus consensus docking site.
What activates a RTK? - CORRECT ANSWER- Ligand/agonist binding
Upon ligand binding the two activation pathways are? - CORRECT ANSWER- 1. Conformational change
- Dimerization
What happens with conformational change activation? - CORRECT ANSWER- A conformational change that is sufficient enough to activate SH1/catalytic domain results in phosphorylation.
What is the only example of conformational change activation? - CORRECT ANSWER- Insulin receptor kinase.
All other RTKs are activated through forms of dimerization.
What are the two forms of dimerization? - CORRECT ANSWER- i) Receptors exist as unactivated dimers until ligand binds (Twist theory)
ii) exist as monomers that are brought together and activated by ligand binding.
What is the most common method of dimerization activation? - CORRECT ANSWER- Receptors existing as monomers.
What is the Twist Theory? - CORRECT ANSWER- RTKs exist as formed dimers and when a ligand binds the dimer undergoes a twist/shift in shape so the catalytic domains can become fully active and therefore allow for autophosphorylation in key tyrosine residues outside the catalytic domain.
What is the monomer dimerization activation pathway? - CORRECT ANSWER- The monomers need to dimerize to fully activate the TK/SH1 domains.
Ligand must bind external domains of two monomer RTKs so they dimerize. This results in increased enzymatic activity of the IC catalytic SH1/TK domains by phosphorylating key tyrosine residues outside the catalytic domain. Transphosphorylation of tyrosines occurs so the kinase activation can occur, and transphosphorylation of regions that create the docking site. The phosphorylated tyrosine residues serve as docking sites for cytoplasmic signalling molecules.
What does RTK activation require? - CORRECT ANSWER- Dimerization and transphosphorylation!!
Where are tyrosines phosphorylated - CORRECT ANSWER- They are first phosphorylated within the kinase/catalytic domains to increase the activity of enzyme and this triggers phosphorylation outside the catalytic/kinase domain that produces a docking site.
What happens when Ras-GAPs when they are mutated? - CORRECT ANSWER- Mutations lead to disease because the Ras-GAPs proteins can't hydrolyze GTP back to GDP efficiently so Ras stays activated longer than it should.
What is SOS? - CORRECT ANSWER- Is a guanine nucleotide exchange factor.
How is Ras linked RTKs? - CORRECT ANSWER- An adaptor protein (Grb-2) and a GEF (SOS) link activated RTKs to Ras (downstrea signalling proteins).
What is Grb-2? - CORRECT ANSWER- Grb-2 is a adaptor (linker) protein that couples activated RTKs to downstream signalling proteins like Ras.
What is Grb-2 composed of? - CORRECT ANSWER- Composed of SH2 and SH3 domains.
What is the function of SH2 domain of Grb-2? - CORRECT ANSWER- SH2 (Src-homology 2) domain of Gr-2 binds to specific phosphotyrosines on activated RTK. Mediates activity.
What is the function of SH3 domain of Grb-2? - CORRECT ANSWER- SH3 is involved in protein interaction and binds to proline rich regions of SOS. SOS is a GEF so it regulates Ras activity.
How are RTKs linked to G-proteins? - CORRECT ANSWER- RTKs are activated and then they are coupled to downstream signalling proteins such as Ras (G-protein). RTK signalling activates G- protein signalling.
RTK activation leads to association with SH2 domain of the linker Grb-2 protein. and the SH domain links with SOS that is a GEF that exchanges GDP for GTP on Ras.
How are Ras and RTK different? - CORRECT ANSWER- Ras is a G-protein that is activated through RTK signalling.
What is the linkage pathway between RTK and G-protein Ras? - CORRECT ANSWER- RTK-(SH2- SH3)-SOS-Ras-Raf
(SH2-SH3) domains constitute the Grb-2 linkage protein. SH3 domain binding to the proline-rich region of SOS brings the GEF from the cytosol to the membrane.
The Grb-2 linker protein does not actually link with the signalling protein, but the exchange factor that activates the G-protein.
What is Raf? - CORRECT ANSWER- Is a MAPKKK. Ras-Associating Factor. Serine/threonine kinase
What is the activation of Raf associated with? - CORRECT ANSWER- Activation is associated with several proteins:
- serine/threonine phosphatase P2A
- Hsp90 chaperone heat shock protein
- Scaffold protein 14-3-
What is the Hsp90 function in activation of Raf? - CORRECT ANSWER- Is a chaperone heat shock protein. It helps to stabilize Raf and is involved in proper cell localization.
What is the scaffold protein 14-3-3 function in Raf
activation? - CORRECT ANSWER- Is a phosphoserine adaptor/chaperone protein. It locks Raf in its inactive formation. It interacts with the RBD N-terminal region bound at two phosphoserine residues on Raf to inhibit Raf activation.
14-3-3 is autoinhibitory.
How does Ras activation lead to Raf dimerization in the Raf/MEK/ERK pathway? - CORRECT ANSWER- Ras forms nanoclusters when activated and promotes Raf dimerization in the Raf/MEK/ERK pathway.
Monomeric Raf is autoinhibited in cytosol.
RBD domain of Raf binding to Ras is a high affinity interaction and releases autoinhibition. Ras- RBD interaction leads to Raf activation through side-by-side dimerization.
What is Raf? - CORRECT ANSWER- Raf (Ras-associating factor) is a MAPKKK = Mitogen activated protein kinase-kinase-kinase. It is a serine/threonine kinase.
What does activated Ras do? - CORRECT ANSWER- Activated Ras recruits MAPKKK (Raf) to the cell membrane and induces a conformational change in MAPKKK that activates its ser/thr kinase activity.
What is another term for MAPKK? - CORRECT ANSWER- MEK
How is MAPKK activated by MAPKKK? - CORRECT ANSWER- MAPKK binds to the c-terminal catalytic domain of Raf (MAPKKK). It is phosphorylated on two serine residues = activation.
What does activated Raf/MAPKKK do? - CORRECT ANSWER- Phosphorylates MAP kinase- kinase at two serine residues to activate it.
What is MAPKK? - CORRECT ANSWER- Is a dual specificity kinase: Has both ser/thr and tyrosine kinase catalytic domains.
What is the substrate of MAPKK? - CORRECT ANSWER- MAPK is the only substrate of MAPKK. It is a tightly regulated response.
What is the function of MAPKK? - CORRECT ANSWER- MAPKK/MEK catalyzes a phosphorylation event on threonine and one on tyrosine to make MAP-kinase (MAPK) fully active.
How is MAPK activated? - CORRECT ANSWER- Only when both threonine and tyrosine are phosphorylated by MEK/MAPKK. It dimerizes.
What is the pathway of Ras activation to activated MAPK? - CORRECT ANSWER- RTK-(SH2- SH3)-SOS-Ras-(RBD-Raf/MAPKKK)-MAPKK/MEK-MAPK
What are the six steps of Ras activation to activated MAPK? - CORRECT ANSWER- 1. Ras activated by exchange of GDP for GTP
- Active Ras recruits, binds, and activates Raf
- GTP hydrolysis leads to dissociation of Ras from Raf
- Raf activates MEK
- MEK activates MAPK
- Dimeric form of active MAPK translocates to nucleus; activates many transcription factors.
What is the function of MAPK? - CORRECT ANSWER- Activates many transcription factors. It induces transcription of c-fos by modifying two transcription factors (TCF and SRF).
What is TCF? - CORRECT ANSWER- A transcription factor.
Ternary Complex factor.
It resides in the nucleus.
What regulates c-fos? - CORRECT ANSWER- Is regulated by MAPK.
How is the RTK-Ras-Raf-MAPK pathway terminated? - CORRECT ANSWER- RTK signalling is downregulated by:
- Protein phosphatatses - PTP1B, SHP1/2 and DEP
- Activated MAPK/ERK1/2 is part of negative feedbac loop. It can phosphorylate SOS which decreases SOS' affinity for GRb-
- Endocytosis, RTK ubiquination
What is Her2/neu/ErbB-2? - CORRECT ANSWER- RTK of EGF class.
What is EGF? - CORRECT ANSWER- Epidermal growth factor. It stimulates proliferation of many cell types.
Is Her-2/neu/ErbB-2 an oncogene? - CORRECT ANSWER- Yes. It has the potential to mutate and contribute to uninhibited proliferation and can induce cell transformation.
It is frequently amplified/over-expressed in human tumours of epithelial origin.
What happens when Her2/neu/ErbB-2(GF) is mutated? - CORRECT ANSWER- Mutations within the TM region can cause constitutive dimerization in an activated state and this, in the case of the ErbB2 receptor can induce cell transformation. It is an oncogene.
Frequently amplified/over-expressed in human tumours of epithelial origin.
What is the amplification or overexpression of Her-2 recognized as? - CORRECT ANSWER- Amplification of Her-2 is a recognized prognostic marker that is associated with poor survival for patients with node-positive breast cancer.
Why is mutation not necessary, but overexpression of Her-2 sufficient to become tumourigenic? - CORRECT ANSWER- If there is overexpression than it leads to ligand independent activation
What is Herceptin? - CORRECT ANSWER- Designer Cancer therapy.
Humanized monoclonal antibody.
What is another name for Herceptin? - CORRECT ANSWER- Trastuzumab.
mab because it is a humanized monoclonal antibody.
How is Herceptin administered? - CORRECT ANSWER- Herceptin is given IV.
Is Herceptin only used for breast cancer? - CORRECT ANSWER- No. It is also in trial for late stage pancreatic cancers that over-express Her2/neu/ErbB.
It is given in combination with the chemotherapeutic drug Gemzar.
How does Herceptin function? - CORRECT ANSWER- It binds to Her-2 and blocks its activation.
How can mutated Ras result in cancer? - CORRECT ANSWER- Mutated Ras can make Ras insentitive to GAP binding, so GTP can't be hydrolyzed to GDP. This results in permanent activation. Resulting in unihibited cellular proliferation.
What types of cancer is Ras mutation associated with? - CORRECT ANSWER- Of the 30% of human tumours that have Ras mutation, pancreatic cancer has the most common incidence (90%), followed by colon (50%), thyroid (50%), lung (30%), ovarian (15%), bladder (6%), breast, skin, liver, kidney and some leukemias.
What is the function of Rigosertib? - CORRECT ANSWER- It is a small molecule that binds to the RBD N terminal of Raf and prevents its association with Ras.
What are three therapeutic targets in the RTK/MAPK pathway? - CORRECT ANSWER- HER2 - Herceptin binds to the RTK and prevents cellular proliferation
FTase Inhibitors - Lonafarnib/Tipifarnib inhibits Ras from binding to the inner membrane and prevents proliferation
RBD of Raf - Rigosertib is a molecule that binds the N terminal and prevents RAS from binding to the RBD of Raf.
How is PI3-K activated? - CORRECT ANSWER- They are activated by binding to specific phospho-tyrosines on activated RTKs.
What is the ultimate goal of PI3-K? - CORRECT ANSWER- It initiates the activation of a major intracellular signalling pathway that promotes cell survival.
PI3-K is responsible for the activation of Akt.
What does PI stand for? - CORRECT ANSWER- Phosphatidylinositol
What is Atk also known as? - CORRECT ANSWER- Protein Kinase B. PKB
What are the components of PI3-K? - CORRECT ANSWER- There are 2 subunits; a regulatory subunit (p85, with SH2 domain) and a catalytic subunit (p110).
What is the characteristics of p85 subunit of PI3-K? - CORRECT ANSWER- There are two SH domains, an N-terminal and a C-terminal domain that recognize phosphorylated tyrosine motifs. There is consesnus.
What is Akt? - CORRECT ANSWER- It is a serine/threonine kinase.
What is the direct action of PI3-K? - CORRECT ANSWER- Due to the close proximity of the RTK associated PI3-K to the PIP2, PI3-K is easily able to phosphorylate PIP2, yielding the lipid 2nd messenger PIP3.
What is PIP2? - CORRECT ANSWER- It is phosphatidylinositol diphosphate. It is embedded in the inner membrane awaiting phoshporylation by PI3-K so that it becomes the second messenger PIP3.
How does PIP3 function in the Akt pathway? - CORRECT ANSWER- PIP3 is able to interact with target proteins via pleckstrin homology (PH) domains found in target proteins. PIP3 is able to traslocate Akt and PDK1 to the membrane.
What are the PIP3 target proteins with PH domains? - CORRECT ANSWER- Akt and Phosphatidylinositide dependent Protein Kinase 1 (PDK1) are colocalized to the plasma membrane.
What is the function of PDK1? - CORRECT ANSWER- PDK1 phosphorylates colocalized Akt on threonine308, leading to partial activation of Akt.
Are there multiple steps to Akt activation? - CORRECT ANSWER- Yes. It is partially activated by PDK1 phosphorylating its Thr308, and fully activated by the mTOR complex phosphorylating Ser473.
What is the mTOR complex composed of? - CORRECT ANSWER- aka mTORC2. Contains the kinase mTOR protein kinase. Phosphoryltes ser473 on Akt.
Once in the nucelus and ubiquinated, FOXO to regulate expression of stress-associated and pro- apoptotic genes.
What happens when FOXO is dephosphorylated in the cytoplasm? - CORRECT ANSWER- During stress, FOXO4 isoform is bound by a uqiquitin molecule and this facilitates its entry into the nucleus.
What does ubiquitin associated to FOXO facilitate? - CORRECT ANSWER- The entry of FOXO to the nucleus.
Also, the interaction with various transcriptional co-activators such as p300 (HAT).
How is stress-induced activation reversed in FOXO activation? - CORRECT ANSWER- There is a ubiquitin specific protease that removes ubiquitin from FOXO so that it stops stress-associated and pro-apoptotic genes.
What is Usp/HAUSP? - CORRECT ANSWER- It is a ubiquitin specific protease that removes ubiquitin from FOXO so that its pro-apoptotic activity is inactivated.
When ismanipulation of the PI3-K pathway used as a cancer treatment? - CORRECT ANSWER- It is a hallmark of endocrine therapy-resistance, hormone receptor-positive breast cancer and Her2 negative. When other interventions are not possible. PI3-K inhibitors are used to induce apoptosis in tumours.
What is BKM120? - CORRECT ANSWER- A PI3-K inhibitor. It targets and antagonizes the PI3-K survival pathwat of the cancer cells.
What are cytokines? - CORRECT ANSWER- Soluble proteins, mainly glycoproteins, or peptides that mediate interactions between cells directly and modulate the individual cells and tissues.
What are cytokines involved in? - CORRECT ANSWER- They regulate hematopoiesis, immunity and development (of many different cell types), and repair of the nervous system.
What types of signalling modalities are cytokines involved in? - CORRECT ANSWER- Autocrine, paracrine and endocrine
What is Epo? - CORRECT ANSWER- Erythropoieitin. It is a cytokine involved in new formation of RBC.
What are Epo receptors? - CORRECT ANSWER- Cytokine receptors
What is CFU-E? - CORRECT ANSWER- Colony forming units erythroid
What is the mechanism of cytokine signalling? - CORRECT ANSWER- Cytokines bind to non receptor tyrosine kinases NRTK (cytosol tyrosine kinases). And the NRTKs phosphorylate variety of intracellular proteins on tyrosine following cytokine R activation.
How does cytokine signalling NRTKs differ from MAPK pathway? - CORRECT ANSWER- NRTKs have a more direct link to transcriptional regulation in the nucleus.
What is a key cytokine signalling pathway? - CORRECT ANSWER- JAK/STAT pathway
What are JAKs? - CORRECT ANSWER- Janus Kinases. They are non-receptor tyrosine kinases.
What do JAKs contain? - CORRECT ANSWER- A carboxyl catalytic kinase domain (SH1 domain, just like RTK).
