1What is the study of how environmental cues are converted into the molecular language cells use to carry out biological functions?
Cell signaling.
2In signal transduction, what are the three principal stages?
Reception (signal binds receptor), Transduction (intracellular cascade), and Response (effector proteins altered).
3Signaling where hormones are carried in the blood to distant target cells is known as _____ signaling.
endocrine
4What type of signaling involves signals released by cells into the extracellular fluid that act locally on adjacent cells?
Paracrine signaling.
5What type of long-range signaling is transmitted along axons to remote target cells?
Synaptic (or neuronal) signaling.
6What form of cell-cell communication requires direct physical touch between the signaling and target cells?
Contact-dependent signaling.
7Signaling in which a cell sends a signal that it also receives is known as _____ signaling.
autocrine
8Why must signaling molecules that bind to intracellular receptors be small and hydrophobic?
To diffuse across the hydrophobic plasma membrane.
9How can cells with identical receptors respond differently to the same signal?
Differences in the internal machinery or effector proteins to which the receptors are coupled.
10Intracellular signaling proteins that can switch between active and inactive states are often referred to as what?
Molecular switches.
11What are the two major classes of proteins that act as molecular switches in signaling pathways?
Protein kinases (signaling by phosphorylation) and GTP-binding proteins.
12What is the largest family of cell surface receptors?
G protein-coupled receptors (GPCRs).
13A GPCR is typically composed of a single polypeptide chain that spans the plasma membrane how many times?
Seven times (it is a seven-pass transmembrane protein).
14What event causes a GPCR to undergo a conformational change that allows it to activate a G protein?
The binding of an extracellular signal molecule.
15What are the three subunits of a trimeric G protein?
Alpha (\$\\alpha\$), beta (\$\eta\$), and gamma (\$\amma\$).
16In its inactive state, the \$\\alpha\$-subunit of a G protein is bound to what molecule?
GDP (guanosine diphosphate).
17What does the activated GPCR act as for the \$\\alpha\$-subunit of the G protein?
A guanine nucleotide exchange factor (GEF).
18The exchange of GDP for GTP on the G protein's \$\\alpha\$-subunit leads to what event?
The dissociation of the activated \$\\alpha\$-subunit from the \$\eta\amma\$ complex.
19How does the G protein's \$\\alpha\$-subunit inactivate itself?
By hydrolyzing its bound GTP to GDP, a process enhanced by RGS proteins.
20What is the function of RGS (Regulator of G protein signaling) proteins?
They act as GTPase-activating proteins (GAPs) for the G protein \$\\alpha\$-subunit, promoting GTP hydrolysis and signal termination.
21What are second messengers?
Small intracellular molecules generated in large amounts in response to receptor activation that diffuse to spread the signal.
22Name two water-soluble second messengers.
Cyclic AMP (cAMP) and inositol 1,4,5-trisphosphate (IP3).
23What is an example of a lipid-soluble second messenger?
Diacylglycerol (DAG).
24The enzyme _____ synthesizes cAMP from ATP.
adenylyl cyclase
25The enzyme _____ breaks down cAMP to terminate its signal.
cAMP phosphodiesterase
26Why is the rapid breakdown of cAMP essential for rapid signaling?
It keeps basal cAMP levels low, allowing for a large and rapid proportional increase upon adenylyl cyclase activation.
27A stimulatory G protein, designated _____, activates adenylyl cyclase.
Gs
28An inhibitory G protein, designated _____, reduces cAMP levels by inhibiting adenylyl cyclase.
Gi
29How does cholera toxin lead to high levels of cAMP?
It modifies the Gs \$\\alpha\$-subunit, locking it in an active, GTP-bound state, which constantly activates adenylyl cyclase.
30In most animal cells, cAMP primarily exerts its effects by activating what enzyme?
Protein kinase A (PKA).
31How does the activation of PKA lead to changes in gene expression?
The active catalytic subunits of PKA can enter the nucleus and phosphorylate transcription regulators like CREB.
32Some G proteins signal by activating the membrane-bound enzyme _____, which acts on an inositol phospholipid.
phospholipase C (PLC)
33What is the primary substrate for phospholipase C in the inositol phospholipid signaling pathway?
Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2].
34Phospholipase C cleaves PI(4,5)P2 to generate which two second messengers?
Inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).
35What is the function of the second messenger IP3?
It binds to and opens IP3-gated Ca²⁺ release channels in the endoplasmic reticulum membrane.
36What is the function of the second messenger diacylglycerol (DAG)?
It remains in the plasma membrane and, along with Ca²⁺, helps activate protein kinase C (PKC).
37Receptor tyrosine kinases (RTKs) are a class of _____ receptors.
enzyme-coupled
38How are most RTKs activated upon ligand binding?
The ligand binding causes the receptors to dimerize.
39What is trans-autophosphorylation in the context of RTK activation?
The process where the kinase domain of one receptor in a dimer phosphorylates tyrosine residues on the other receptor.
40What are the two main effects of RTK autophosphorylation?
It fully activates the kinase domains and creates docking sites for intracellular signaling proteins.
41Which type of protein domain commonly recognizes and binds to phosphotyrosine residues on activated RTKs?
SH2 domains.
42What is the name of the small, monomeric GTPase that is frequently activated downstream of RTKs?
Ras.
43Ras is active when bound to _____ and inactive when bound to _____.
GTP; GDP
44Which type of protein activates Ras by promoting the exchange of GDP for GTP?
Ras-GEF (Guanine nucleotide Exchange Factor), such as Sos.
45Which type of protein inactivates Ras by promoting the hydrolysis of GTP to GDP?
Ras-GAP (GTPase-Activating Protein).
46How does an activated RTK typically lead to the activation of Ras?
An adaptor protein (like Grb2) binds to the RTK and recruits a Ras-GEF (like Sos) to the plasma membrane, where it can activate Ras.
47Why is it more energy-efficient for signaling pathways to activate Ras by activating a GEF rather than inactivating a GAP?
Inactivating a GAP would require constant, wasteful GTP hydrolysis to keep Ras off in the absence of a signal.
48Activated Ras initiates a phosphorylation cascade known as the _____ signaling module.
MAP kinase
49List the three core kinases in the MAP kinase cascade in order of activation.
MAP kinase kinase kinase (Raf), MAP kinase kinase (Mek), and MAP kinase (Erk).
50What is the role of a scaffolding protein in a kinase cascade?
It holds the kinases in a complex, increasing signal transmission speed and preventing cross-talk, but limits signal amplification.
51What is a major advantage of a kinase cascade involving freely diffusing kinases over one organized by a scaffold?
It allows for greater signal amplification.
52What is a form of regulation where a downstream component of a pathway inhibits an upstream component?
Negative feedback.
53In the Raf pathway, Erk can phosphorylate and inhibit the upstream RTK. What is the effect of using a drug that inhibits Raf?
It leads to decreased Erk activity, which in turn reduces the inhibitory phosphorylation of the RTK, causing a rebound in RTK signaling.
54The PI 3-kinase-Akt pathway is primarily involved in promoting what two cellular processes?
Cell survival and growth.
55What is the function of PI 3-kinase when activated by an RTK?
It phosphorylates the 3 position of inositol rings on inositol phospholipids, creating docking sites.
56Activated Akt promotes cell survival by phosphorylating and inactivating which pro-apoptotic protein?
Bad.
57The inactivation of Bad allows which protein to become active and inhibit apoptosis?
Bcl2, an apoptosis-inhibitory protein.
58How is Akt fully activated after being recruited to the plasma membrane?
It is phosphorylated by both mTOR (in complex 2) and PDK1.
59How does phosphorylation by TOR contribute to Akt activation?
It alters Akt's conformation, making it accessible for phosphorylation by PDK1.
60What is cancer?
A disease resulting from a cell breaking free from normal controls, leading to uncontrolled division.
61Normal genes that are responsible for making cells divide are known as _____.
proto-oncogenes
62A mutated version of a gene that normally promotes cell division, leading to uncontrolled growth, is called an _____.
oncogene
63The analogy for an oncogene's effect on cell division is a gas pedal that is _____.
stuck in the on position
64Genes whose products function as the equivalent of cellular brakes to stop cell division are known as _____.
tumor suppressors
65Why must both copies of a tumor suppressor gene typically be damaged for a cell to lose its ability to stop dividing?
Because one functional copy is usually sufficient to stop the cell from behaving abnormally (it is recessive).
66What are the three most common mutational hotspots in RAS genes that lead to oncogenic activity?
Codons G12, G13, and Q61.
67How do oncogenic mutations in Ras typically make the protein hyperactive?
They abolish the intrinsic GTPase activity of Ras, trapping it in a continuously active, GTP-bound state.
68Approximately what percentage of all human cancers are driven by mutations in RAS genes?
Around 19-30%.
69Which RAS isoform is most frequently mutated in human cancers?
KRAS.
70The process by which tumors induce the body to form new blood vessels to supply them with nutrients is known as _____.
angiogenesis
71What is the term for the movement of tumor cells to other parts of the body to form new tumors?
Metastasis.
72What is the name for the orderly process of programmed cell death, or cellular suicide, that is often lost in cancer cells?
Apoptosis.
73Disregulated MAPK signaling, often caused by Ras or Raf mutations, can lead to increased cell proliferation and resistance to _____.
apoptosis (or programmed cell death)
74What is a key difference in the activation mechanism of the insulin receptor compared to most other RTKs?
The insulin receptor exists as a pre-formed dimer; ligand binding causes a conformational change rather than inducing dimerization.
75How does the Epidermal Growth Factor (EGF) receptor's kinase domain become activated?
Dimerization orients the kinase domains asymmetrically, where one (the activator) pushes against and activates the other (the receiver).
76Targeted therapies like AMG510 (sotorasib) are designed to specifically inhibit which mutant form of KRAS?
KRASG12C.
77How do KRASG12C inhibitors like sotorasib work?
They form a covalent bond with the cysteine residue at position 12, trapping the KRAS protein in its inactive, GDP-bound state.
78Why do some BRAF inhibitors paradoxically activate the MAPK pathway in cells with wild-type BRAF and mutant Ras?
The inhibitors drive RAS-dependent binding of BRAF to CRAF, leading to CRAF-mediated activation of the pathway.