MODULE 8: Chapter 8.3 Flashcards
What is the function of receptor tyrosine kinases (RTKs)?
Transmit extracellular signals by ligand activation of an intrinsic tyrosine kinase function
What does EGFR stand for?
Epidermal growth factor receptor
What is the role of Akt in RTK signaling?
Enzyme with kinase activity, also known as protein kinase B (PKB)
Fill in the blank: The intrinsic kinase of RTKs phosphorylates ______ residues.
tyrosine
What type of proteins do RTK target proteins often serve as?
Adaptor proteins
What are the two best-characterized RTK signaling pathways?
Epidermal growth factor receptor (EGFR) and insulin receptor
What is the main consequence of RTK signaling pathways?
Increased cell division
How many amino acids does epidermal growth factor (EGF) have?
53
What structural feature does EGF possess?
Three disulfide bridges
What is the function of the SH2 domain?
Binds phosphotyrosine residues
True or False: GRB2 is an adaptor protein that binds to pY residues.
True
What does RasGAP do?
Stimulates the intrinsic GTPase activity in Ras
What is the first kinase in the MAP kinase pathway?
Raf
Fill in the blank: The MAP kinase pathway is involved in ______ regulation.
gene expression
What type of activity does Ras possess?
GTPase activity
What is the role of MEK in the MAP kinase pathway?
Phosphorylates the third kinase, ERK
What is the final cellular response to the MAP kinase signaling pathway?
Increased rates of cell division
What do defects in RTK signaling pathways often lead to?
Human diseases, including cancer
What type of mutations are commonly linked to human cancers?
Somatic mutations in cell signaling genes
What is the primary function of the enzyme phosphoinositide 3-kinase (PI3K)?
Key role in insulin signaling
What is the significance of the term ‘mitogen’ in the context of MAP kinase signaling?
A compound that activates mitosis
What is the relationship between GRB2 and SOS?
GRB2 recruits SOS to activate Ras
What happens to activated ERK in the signaling pathway?
Translocates to the nucleus to regulate gene expression
What are the two major types of somatic mutations found in humans?
Gain-of-function oncogene mutations and loss-of-function oncogene mutations
Gain-of-function mutations are also called dominant mutations, while loss-of-function mutations are recessive.
What is the significance of oncogenes in cancer?
Oncogenes are cancer-causing genes that result from mutations in normal cell signaling genes.
The discovery of oncogenes was made by J. Michael Bishop and Harold E. Varmus.
What is the role of the retinoblastoma gene?
It is a tumor suppressor gene that inhibits uncontrolled cell proliferation.
Inactivating mutations in this gene lead to retinoblastoma cancer.
True or False: A dominant gain-of-function mutation requires both gene copies to be mutated to cause cancer.
False
A dominant mutation only requires one copy to lead to a disease phenotype.
What is the most common type of cancer mutation?
Dominant gain-of-function mutations
These mutations result in new activity in the cell, such as uncontrolled growth.
What is an example of a common oncogenic mutation in Ras proteins?
Missense mutations that decrease the intrinsic GTPase activity.
Common mutations include G12D, G12V, and G12R.
Fill in the blank: The insulin receptor consists of an ______ complex.
α2β2 tetrameric
The α and β subunits are linked by disulfide bonds.
What are the two major downstream pathways controlled by insulin receptor signaling?
Increased glucose uptake and glycogen synthesis, and stimulation of cell division.
These pathways are activated through IRS and Shc proteins.
What triggers the activation of the insulin receptor?
Binding of a single insulin molecule
This binding induces a conformational change that activates the receptor.
What are IRS proteins and their role in insulin signaling?
Insulin receptor substrate proteins that bind to phosphotyrosine residues in the insulin receptor and activate downstream signaling pathways.
IRS-1 is predominant in muscle cells, while IRS-2 is predominant in liver cells.
What is the function of PI3K in insulin signaling?
It phosphorylates PIP2 to produce PIP3, leading to increased glucose uptake and glycogen synthesis.
PI3K is activated by tyrosine-phosphorylated IRS proteins.
What is the role of PTEN in PI3K signaling?
PTEN terminates PI3K signaling by removing the phosphate from PIP3 to regenerate PIP2.
Mutations in PTEN can lead to uncontrolled cell growth in tumors.
What is the significance of negative cooperativity in insulin receptor signaling?
Binding of one insulin molecule inhibits the binding of a second insulin molecule.
This is different from positive cooperativity observed in hemoglobin.
What are the three tyrosine residues that must be autophosphorylated in the insulin receptor to activate its substrate kinase activity?
pY1158, pY1162, pY1163
These residues are part of the tyrosine kinase domain.
What happens to the MAP kinase pathway when the insulin receptor signaling is activated?
It stimulates altered gene expression and cell division.
This occurs through Shc-mediated activation of the pathway.
What is a common characteristic of gain-of-function mutations in cancer cells?
They promote cell growth in the absence of regulatory signals that control cell growth.
These mutations can affect both PI3K and MAP kinase pathways.
What activates the MAP kinase signaling pathway?
Function mutations through Ras mutations
Which domains in signaling proteins bind to membrane-associated lipids?
Pleckstrin homology (PH) domains
What is the role of PIP3 in the insulin signaling pathway?
Serves as a docking site for signaling proteins containing PH domains
Name two proteins in the insulin signaling pathway that bind to PIP3.
- Phosphoinositide-dependent kinase-1 (PDK1)
- Akt (protein kinase B)
What is the function of Akt in liver cells?
Initiates downstream signaling pathways resulting in glucose import and glycogen synthesis
How does insulin signaling affect blood glucose levels?
Lowers blood glucose levels by removing glucose from circulation
What is the opposite effect of insulin signaling in liver cells?
Glucagon signaling increases glucose export
What are the four types of binding domains required for EGF and insulin signaling?
- SH2 domains
- SH3 domains
- PTB domains
- PH domains
True or False: SH2 domains bind to phosphotyrosine residues.
True
Fill in the blank: A glycine residue at position 12 of the G protein Ras is only active in the presence of _______.
[growth factors]
What is an oncogene?
A mutated version of a normal gene that can cause cancer
What type of mutation requires only one copy of the gene to be mutated to display a phenotype?
Dominant mutation
What is a recessive mutation?
Requires both copies of the gene to be mutated to display a phenotype
What is the role of the tumor suppressor gene?
Inhibits uncontrolled cell proliferation
What does the phosphotyrosine binding (PTB) domain bind to?
Phosphotyrosine residues on target proteins
What is the function of the insulin receptor substrate (IRS)?
Binds to phosphorylated insulin receptors through phosphotyrosine binding domains
What does the pleckstrin homology (PH) domain bind to?
PIP3 in the plasma membrane
What is the function of phosphoinositide-dependent kinase-1 (PDK1)?
Binds to PIP3 and phosphorylates Akt
What does Src kinase homology-2 (SH2) domain bind to?
A specific amino acid sequence containing a phosphotyrosine residue
What is the role of growth factor receptor–bound 2 (GRB2)?
An SH2/SH3 adaptor protein that binds to the EGF receptor
What does Src kinase homology-3 (SH3) bind to?
Specific proline-rich sequences
What are mitogen-activated protein kinases (MAP kinases) involved in?
Activating a phosphorylation cascade leading to increased rates of cell division
What is phosphatidylinositol-3,4,5-trisphosphate (PIP3)?
A glycolipid that recruits proteins with a PH domain to the plasma membrane
What does phosphatase and tensin homolog (PTEN) do?
Removes a phosphoryl group from PIP3 to regenerate PIP2
