Week 4/5 - Growth Factor Signaling and Oncogenes

Flashcards covering key concepts related to normal growth factor signaling, EGF pathway steps, oncogenes, retroviruses, and specific mutated proteins like RAS, RET, B-RAF, and SRC, as derived from the lecture notes.

What is the primary role of normal growth factor signaling in a cell?

It is necessary for cell division to occur, involving precise DNA replication to maintain genome integrity.

How does signal transduction allow external signals to influence a cell?

It transmits a signal through the membrane, cytoplasm, and into the nucleus to regulate gene expression, resulting in the production of required proteins.

Name the four types of proteins involved in normal growth factor signaling.

Growth factors, growth factor receptors, intracellular signal transducers, and nuclear transcription factors.

What kind of receptors are many Epidermal Growth Factor Receptors (EGFR), and what do they catalyze?

Many EGFRs are tyrosine kinase receptors that catalyze the transfer of a phosphate group from ATP/GTP to a hydroxyl group on a specific amino acid in a target protein.

What are the three general domains found in EGFR receptor proteins?

An extracellular ligand-binding domain, a transmembrane domain, and a cytoplasmic protein tyrosine kinase domain.

List the immediate sequential steps that occur after a growth factor binds to its receptor in signal transduction.

Receptor dimerization, followed by autophosphorylation.

What is the kinase cascade activated in the sequential steps of signal transduction?

RAF phosphorylates MEK, which then phosphorylates MAPK.

What is the significance of autophosphorylation on the cytoplasmic domain of receptors?

It is crucial for the recruitment of cytoplasmic substrate proteins that will pass the signal from the receptor to the signal transducers, effectively transducing the signal inside the cell.

What are oncogenes and how do they typically originate?

Oncogenes are altered (mutated) forms of normal genes (proto-oncogenes) that retain their functionality but are no longer capable of responding to normal regulatory signals, representing a gain of function mutation.

How can receptor mutations lead to uncontrolled cell division?

This can occur through extracellular domain deletion (triggering cell division without a ligand), point mutations (interfering with growth factor binding and inducing constitutive 'always on' activation), or gene amplification (increasing receptor proteins for increased growth signaling).

What is the normal function of the RET proto-oncogene?

RET encodes a receptor tyrosine kinase and plays an important role in kidney development and neuronal differentiation.

In what type of cancer are somatic chromosomal rearrangements involving RET frequently found, particularly following high radiation exposure?

Papillary thyroid carcinoma cells.

Why is RAS considered the most commonly mutated oncogene in human tumors?

Oncogenic activation of RAS is seen in approximately 30% of human tumors, and mutations lead to the loss of GTPase activity causing constitutive activation.

What role do GRB and SOS proteins play after receptor autophosphorylation in the EGF pathway?

The phosphorylated receptor recruits GRB protein (an adaptor), which then introduces SOS protein (a RAS guanine nucleotide exchange factor), leading to SOS activating RAS by exchanging GDP with GTP.

List two mechanisms by which the activity of a tyrosine kinase receptor can be terminated.

Additional phosphorylation that inhibits ligand binding and kinase activity; dephosphorylation by phosphatases; binding of negative regulators to the kinase domain; or receptor endocytosis and degradation.

How is RAS activated and deactivated in the cell?

RAS is inactive ('off') when bound to GDP and active ('on') when bound to GTP. Guanine nucleotide exchange factors (GEF) like SOS mediate the exchange of GDP for GTP to activate it, while GTPase activation proteins (GAPs) regulate its deactivation.

Describe the kinase cascade initiated by activated RAS in the late steps of the EGF pathway.

RAS-GTP recruits and activates RAF, which then phosphorylates and activates MEK. MEK subsequently phosphorylates and activates MAPK.

What is the final action of activated MAPK in the nucleus?

Activated MAPK enters the nucleus, phosphorylates, and activates transcription factors (TF) that turn on specific sets of genes needed for cell growth.

What is the purpose of cell transformation assays?

They are used to identify oncogenes and their specific mutations, often by observing the formation of foci (colonies) of transformed cells.

What is a common oncogenic mutation of B-RAF and its effect?

The BRAF V600E mutation, common in melanoma, results in constitutive kinase activity and insensitivity to feedback mechanisms, initiating growth signaling inappropriately.

What is the function of the MYC protein and what is required for it to function?

MYC is a short-lived protein that promotes proliferation by regulating the expression of specific target genes. It requires the constitutively expressed family member MAX to function.

What is the role of the SRC intracellular tyrosine kinase in cell behavior, especially when EGFR activation occurs?

SRC plays an important role in the regulation of cell adhesion, invasion, and motility; its activation results in reduced cell adhesion and increased cell motility.

How does SRC activation impact focal adhesions and cell motility?

SRC activation facilitates the disassembly of focal adhesions (cell-matrix junctions), which in turn facilitates increased cell motility.