15) Cell Signaling

A genetic form of "night blindness" (i.e. poor vision in dim light) is caused by mutations in genes encoding rhodopsin kinase (RK) and arrestin. The mutations reduce the dynamic range of light perception, and the affected individuals have a prolonged light response and adapt very slowly to low light (when entering a dark theater room, for example). Which of the following mutations do you expect to be the cause? A. Loss-of-function RK mutations and loss-of-function arrestin mutations B. Loss-of-function RK mutations and gain-of-function arrestin mutations C. Gain-of-function RK mutations and loss-of-function arrestin mutations D. Gain-of-function RK mutations and gain-of-function arrestin mutations

1. Answer: A Difficulty: 2 Section: Signaling through G-Protein-Coupled Receptors Feedback: Mice or humans with defects in RK, or its downstream regulator arrestin, have a prolonged light response, incapable of adapting quickly to sudden drops in ambient light intensity.

A cell expresses a transmembrane protein that is cleaved at the plasma membrane to release an extracellular fragment. The fragment binds to receptor proteins on nearby cells and activates signaling pathways resulting in altered gene expression patterns in the cells. What form of intercellular signaling does this represent? A. Contact-dependent signaling B. Paracrine signaling C. Synaptic signaling D. Endocrine signaling E. Autocrine signaling

1. Answer: B Difficulty: 1 Section: Principles of Cell Signaling Feedback: Paracrine signaling acts on neighboring cells via local mediators.

Which of the following mechanisms is NOT employed by I-Smads to negatively regulate Smad signaling? A. Competing with R-Smads for binding sites on the receptor, decreasing R-Smad phosphorylation. B. Recruiting the ubiquitin ligase Smurf, leading to receptor degradation. C. Binding to caveolin, inhibiting the formation of caveolae. D. Binding to the co-Smad, Smad4, inhibiting it. E. Recruiting protein phosphatases, leading to receptor inactivation.

1. Answer: C Difficulty: 2 Section: Signaling through Enzyme-Coupled Receptors Feedback: Activated TGFβ receptors can be endocytosed by two distinct routes: one is dependent on clathrin-coated vesicles and leads to further activation, whereas the other one depends on caveolae and leads to inactivation. Inhibiting the formation of caveolae can therefore activate, rather than, inhibit TGFβ signaling.

Consider visual transduction in rod photoreceptors in the vertebrate retina. Which of the following steps does NOT normally amplify the signal in this pathway? A. Activation of transducin by active rhodopsin B. Blockage of Na+ influx by cation-channel closure C. Cation-channel closure due to cGMP depletion D. Depletion of cGMP by active cGMP phosphodiesterase E. All of the above DO involve amplification

1. Answer: C Difficulty: 2 Section: Signaling through G-Protein-Coupled Receptors Feedback: A single quantum of light can result in the hydrolysis of more than 105 cyclic GMP molecules in the visual transduction cascade. This closes only a few hundred cyclic-GMP-sensitive channels.

Consider a signaling protein that is only made up of one SH2 domain and two SH3 domains. This protein is most likely ... A. a monomeric G protein. B. a guanine nucleotide exchange factor. C. a kinase associated with receptor tyrosine kinase signaling. D. an adaptor protein. E. a negative regulator of receptor tyrosine kinase signaling.

1. Answer: D Difficulty: 1 Section: Signaling through Enzyme-Coupled Receptors Feedback: An example of such a protein is Grb2, an adaptor protein involved in signaling by receptor tyrosine kinases.

Proteins of the Src family (e.g. Src, Fyn, Lck, and Hck) have important roles in several signaling pathways in mammals. A typical Src family protein ... A. is a cytosolic tyrosine kinase. B. contains SH2 and SH3 domains in addition to a kinase domain. C. has covalently attached lipid chains. D. is located on the cytoplasmic side of the plasma membrane. E. All of the above.

1. Answer: E Difficulty: 1 Section: Signaling through Enzyme-Coupled Receptors Feedback: Src family proteins are cytosolic tyrosine kinases exemplified by Src. They contain SH2 and SH3 domains and can associate with the cytoplasmic side of the plasma membrane partly by covalently attached lipid chains.

Indicate true (T) and false (F) statements below regarding the Ras-MAP-kinase signaling pathway. Your answer would be a four-letter string composed of letters T and F only, e.g. TTTF. ( ) The immediate early genes turn on a few hours after activation of the RTK. ( ) Ras-GTP binds directly to, and activates, the upstream kinase in the MAP kinase module. ( ) Signal transduction through the Ras-MAP-kinase pathway only leads to a transient response. ( ) In the MAP kinase module, Raf can be phosphorylated by Erk to create a negative feedback loop.

1. Answer: FTFT Difficulty: 2 Section: Signaling through Enzyme-Coupled Receptors Feedback: The mitogen-activated protein kinase (MAP kinase) module in the mammalian Ras-MAP-kinase signaling pathway is composed of Raf, Mek, and Erk. Stimulation of receptor tyrosine kinases (RTKs) at the cell surface can activate Ras, which then triggers the MAP kinase cascade. Once activated, Erk relays the signal downstream, leading to transient or long-lasting responses. Erk can also regulate Raf activity through negative feedback loops. The immediate early genes are typically activated minutes after RTK stimulation.

Indicate whether each of the following descriptions better applies to phytochromes (P), cryptochromes (C), or phototropins (T). Your answer would be a four-letter string composed of letters P, C, and T only, e.g. TPCC. ( ) They respond to red light. ( ) They are found in animals as well as in plants. ( ) They are flavoproteins. ( ) They are dimeric, cytosolic serine/threonine protein kinases that are normally activated by autophosphorylation.

1. Answer: PCCP Difficulty: 1 Section: Signaling in Plants Feedback: Phytochromes are cytosolic serine/threonine protein kinases that are activated by red light. Cryptochromes are flavoproteins that are sensitive to blue light. They are found in animal as well as in plant cells.

For the α subunit of a trimeric G protein, ... A. a G-protein-coupled receptor (GPCR) acts as a guanine nucleotide exchange factor (GEF), whereas a regulator of G protein signaling (RGS) can act as a GTPase-activating protein (GAP). B. a GPCR acts as a GAP, whereas an RGS can act as a GEF. C. both a GPCR and an RGS can act as a GEF. D. both a GPCR and an RGS can act as a GAP.

1. Answer: A Difficulty: 2 Section: Signaling through G-Protein-Coupled Receptors Feedback: The GPCR and the RGS act in opposite directions with regards to the activation of trimeric G proteins, by acting as a GEF and a GAP, respectively.

All nuclear receptors ... A. are cytosolic proteins that enter the nucleus upon ligand binding. B. have ligand-binding and DNA-binding domains, and can directly bind to DNA. C. are transcriptional activators when bound to their ligand. D. bind to steroid hormones. E. are transcriptional repressors in the absence of their ligand.

1. Answer: B Difficulty: 1 Section: Alternative Signaling Routes in Gene Regulation Feedback: Nuclear receptors have at least a ligand-binding domain and a DNA-binding domain. Some of them only enter the nucleus after ligand binding, whereas others are present inside the nucleus even in the absence of their ligand. Their ligands are typically small hydrophobic molecules such as steroid hormones and thyroid hormones. Some nuclear receptors are transcriptional activators, whereas others are transcriptional repressors.

What is the major way by which the monomeric G protein Ras is activated in receptor tyrosine kinase signaling? A. Activation of Ras-GAP B. Activation of Ras-GEF C. Inactivation of Ras-GAP D. Inactivation of Ras-GEF E. Inactivation of Ras-GDI

1. Answer: B Difficulty: 1 Section: Signaling through Enzyme-Coupled Receptors Feedback: Ras is activated by guanine nucleotide exchange (GDP release and GTP binding), which is catalyzed by upstream Ras guanine nucleotide exchange factors (Ras-GEFs). In contrast, Ras GTPase-activating proteins (Ras-GAPs) increase the rate of GTP hydrolysis by Ras and therefore inactivate it. Guanine nucleotide dissociation inhibitors (GDIs) prevent the association of some GTPases with their GEFs, thereby keeping the GTPases inactive.

What is the effect of using scaffold proteins on precision and amplification capacity in cell signaling? A. Both precision and amplification are improved. B. Precision is improved, but amplification is limited. C. Precision is compromised, but amplification is improved. D. Both precision and amplification are limited.

1. Answer: B Difficulty: 1 Section: Signaling through Enzyme-Coupled Receptors Feedback: Scaffold proteins help prevent cross-talk and improve precision in signaling pathways, but they also limit diffusion of pathway components and thereby reduce the opportunities for amplification and spreading of the signal to different parts of the cell.

Which of the following proteins lacks a PH domain? A. Sos (a Ras-GEF) B. Grb2 (an RTK signaling adaptor) C. Pleckstrin (a protein kinase C substrate) D. Akt (protein kinase B) E. PDK1 (phosphoinositide-dependent kinase)

1. Answer: B Difficulty: 2 Section: Signaling through Enzyme-Coupled Receptors Feedback: Mainly functioning in protein-protein interaction, PH domains are found in many signaling proteins, including pleckstrin, Akt, PDK1, and Sos.

Which of the following is NOT part of a negative feedback mechanism in adaptation to light in retinal rod cells? A. Phosphorylation of G-protein-coupled receptor B. Binding of arrestin to G protein C. Stimulation of guanylyl cyclase by decreased Ca2+ levels D. Binding of regulator of G protein signaling to transducin

1. Answer: B Difficulty: 2 Section: Signaling through G-Protein-Coupled Receptors Feedback: Following the phosphorylation of the receptor by rhodopsin kinase, arrestin binds to it to prevent transducin activation. Other mechanisms, such as binding of RGS (regulator of G protein signaling) to the G protein α subunit or activation of guanylyl cyclase, are also involved in visual adaptation in rod cells.

How does the expression of Delta on the surface of a cell activate the expression of certain genes in the nucleus of its neighboring cell? A. Delta binding activates Notch, which activates a transcriptional activator through the JAK-STAT pathway. B. Delta binding leads to the stabilization of a cytoskeleton-associated transcriptional activator. C. Delta binding releases the intracellular tail of Notch, which enters the nucleus and converts a transcriptional repressor into a transcriptional activator. D. Delta binding leads to Notch-mediated recruitment of protein complexes to the plasma membrane, resulting in the degradation of a transcriptional repressor. E. Delta binding leads to the proteolytic cleavage of Notch and inhibition of its activity as a transcriptional repressor, leading to the activation of target genes.

1. Answer: C Difficulty: 1 Section: Alternative Signaling Routes in Gene Regulation Feedback: Upon Notch binding to Delta, a plasma-membrane-bound protease cleaves off a cytoplasmic segment of Notch, which enters the nucleus to activate the expression of target genes. The fragment acts by binding to a DNA-binding protein and converting it from a transcriptional repressor into a transcriptional activator.

Which of the following events normally activates a GTP-binding protein? A. GTP hydrolysis by the protein B. Activation of an upstream GTPase-activating protein C. Activation of an upstream guanine nucleotide exchange factor D. Phosphorylation of a bound GDP molecule by an upstream phosphorylase E. Pi release after GTP hydrolysis

1. Answer: C Difficulty: 1 Section: Principles of Cell Signaling Feedback: Activation of an upstream guanine nucleotide exchange factor (GEF) activates a GTPase by facilitating its conversion into a GTP-bound form through guanine nucleotide exchange.

The SH2 domain of STAT proteins plays a key role in cytokine receptor signaling. This domain can bind to phosphotyrosine ... A. on an activated receptor molecule, or (intramolecularly) on the same STAT molecule. B. on a Janus kinase molecule, or (intramolecularly) on the same STAT molecule. C. on an activated receptor molecule, or on another STAT molecule in a dimer. D. on a Janus kinase molecule, or on another STAT molecule in a dimer. E. on the same STAT molecule or on another STAT molecule in a dimer.

1. Answer: C Difficulty: 1 Section: Signaling through Enzyme-Coupled Receptors Feedback: Each STAT has an SH2 domain with two functions: it mediates STAT binding to an activated cytokine receptor; after JAK phosphorylation of STAT, it mediates binding between two STAT molecules in a dimer.

PI 3-kinase ... A. is a membrane-associated tyrosine kinase. B. activates PDK1 by phosphorylating a serine residue on the protein. C. is counteracted by PTEN phosphatase. D. is only known to be activated by receptor tyrosine kinases. E. inhibits Akt.

1. Answer: C Difficulty: 1 Section: Signaling through Enzyme-Coupled Receptors Feedback: The plasma-membrane-bound PI 3-kinase principally phosphorylates inositol phospholipids rather than proteins. It can be activated downstream of receptor tyrosine kinases or G-protein-coupled receptors, and generates docking sites for various signaling proteins. PTEN phosphatase counteracts PI 3-kinase by dephosphorylating the 3 position of the inositol ring.

Which of the following is a major consequence of activation of phospholipase C-β (PLCβ) by the Gq trimeric GTPase? A. Elevation of intracellular cAMP levels, leading to the activation of protein kinase A B. Elevation of PIP3 levels in the plasma membrane, leading to the activation of protein kinase B C. Elevation of intracellular Ca2+ levels, leading to the activation of protein kinase C D. Elevation of IP3 in the plasma membrane, leading to the activation of protein kinase D E. Elevation of intracellular cGMP levels, leading to the activation of protein kinase G

1. Answer: C Difficulty: 1 Section: Signaling through G-Protein-Coupled Receptors Feedback: Stimulation of protein kinase C (PKC) activity near the plasma membrane results from elevated cytosolic Ca2+ [induced by inositol 1,4,5-trisphosphate (IP3) production] and from binding to diacylglycerol and negatively charged phospholipids. IP3 and diacylglycerol are second messengers in the cytosol and plasma membrane, respectively, and are produced from phosphatidylinositol 4,5-bisphosphate by the action of PLCβ.

Whereas the cholera toxin ADP-ribosylates the α subunit of stimulatory G protein (Gs), thereby blocking GTP hydrolysis, pertussis toxin ADP-ribosylates the α subunit of inhibitory G protein (Gi) and prevents interaction with the receptor. What is the effect of these toxins on the concentration of intracellular cAMP? A. Cholera toxin tends to increase cAMP concentration, whereas pertussis toxin tends to decrease cAMP concentration. B. Cholera toxin tends to decrease cAMP concentration, whereas pertussis toxin tends to increase cAMP concentration. C. They both tend to increase cAMP concentration. D. They both tend to decrease cAMP concentration.

1. Answer: C Difficulty: 2 Section: Signaling through G-Protein-Coupled Receptors Feedback: While cholera toxin causes constitutive Gs activation, pertussis toxin prevents Gi activation. Both of these result in a net activation of adenylyl cyclase, leading to higher cAMP levels. Note that adenylyl cyclase is not the only target of Gi.

Which of the following is NOT a common second messenger in cell signaling? A. Ca2+ B. Cyclic adenosine monophosphate C. Diacylglycerol D. Tyrosine E. Inositol trisphosphate

1. Answer: D Difficulty: 1 Section: Principles of Cell Signaling Feedback: Second messengers are small chemicals generated in large amounts in response to receptor activation in signaling pathways and diffuse away from their source to spread the signal. Some are water-soluble [e.g. calcium ions and cyclic adenosine monophosphate (cAMP)] and some are lipid-soluble [e.g. diacylglycerol (DAG) and inositol trisphosphate (IP3)].

Ethylene receptors in plant cells ... A. are located primarily at the plasma membrane. B. are single-pass transmembrane proteins. C. interact with CTR1, which is closely related to the monomeric G protein Ras. D. have a copper-containing ethylene-binding domain. E. All of the above.

1. Answer: D Difficulty: 1 Section: Signaling in Plants Feedback: Ethylene receptors in plant cells are dimeric multipass transmembrane proteins primarily located in the endoplasmic reticulum. In addiction to a copper-containing ethylene-binding domain, they contain a cytosolic domain that interacts with CTR1, a serine/threonine kinase related to Raf, an upstream kinase in the MAP kinase module in animal cells.

How is the activation of epidermal growth factor receptor (EGFR) different from that of insulin receptor (IR)? A. EGFR is a dimer in its inactive and active forms, whereas IR dimerizes only when active. B. EGFR activation requires dimerization, whereas IR can become activated as a monomer. C. EGFR is activated by transautophosphorylation, whereas IR activation is phosphorylation-independent and is a simple consequence of receptor dimerization. D. Unlike IR activation, EGFR activation involves an asymmetric arrangement of the intracellular kinase domains. E. Both C and D above.

1. Answer: D Difficulty: 2 Section: Signaling through Enzyme-Coupled Receptors Feedback: Dimerization of the insulin receptor brings the two kinase domains close to each other such that they can phosphorylate each other in the active site. In the case of the EGF receptor, the kinase is activated by the conformational change induced by asymmetric interactions between the two kinase domains outside their active sites.

Sort the following events to reflect the normal order in which they occur in G-protein-coupled receptor signaling leading to transcription of genes with cAMP response elements. Your answer would be a four-letter string composed of letters A to E only, e.g. ACBD. (A) Binding of CREB to PKA (B) Binding of cAMP to PKA (C) Dissociation of PKA into catalytic and regulatory subunits (D) Activation of adenylyl cyclase

1. Answer: DBCA Difficulty: 1 Section: Signaling through G-Protein-Coupled Receptors Feedback: Upon cAMP production by activated adenylyl cyclase, cAMP-dependent protein kinase (PKA) is activated through the release of its catalytic subunits as a result of cAMP binding to the regulatory subunits. The catalytic subunits then enter the nucleus where they phosphorylate CREB (cAMP response element-binding protein), which recruits other proteins to activate transcription of target genes.

Cells can adapt to extracellular signal molecules in a variety of ways. Interestingly, exposure to a signal molecule can sometimes not only desensitize the cell to this molecule, but also to one or more other signal molecules that are recognized by different receptors, even if those receptors can still bind to their ligand at the cell surface and initiate signaling. Which subset of the following adaptation mechanisms (for the original signal) can in principle account for this type of desensitization? Choose all that apply. Your answer would be a string composed of letters A to E only, in alphabetical order; e.g. BDE. (A) Receptor sequestration (B) Receptor down-regulation (C) Receptor inactivation (D) Inactivity of signaling protein (E) Production of inhibitory protein

1. Answer: DE Difficulty: 2 Section: Principles of Cell Signaling Feedback: If the signaling pathways for the signals converge (or overlap), adaptation to one signal can also desensitize the cell to the others by affecting the common signaling molecules. In this example, convergence occurs downstream of the receptors; therefore, the first three mechanisms do not apply. Note that the first three adaptation mechanisms act on the receptor for the original signal, not on other receptors.

Sort the following events into the order that they take place in phototransduction in response to a flash of light. Your answer would be a four-letter string composed of letters A to E, e.g. BCDEA. (A) The cGMP level drops. (B) The cGMP level rises. (C) The Ca2+ level drops. (D) Retinal isomerizes to an all-trans configuration. (E) Gt exchanges its bound nucleotide.

1. Answer: DEACB Difficulty: 2 Section: Signaling through G-Protein-Coupled Receptors Feedback: Light stimulation of rod photoreceptors isomerizes 11-cis retinal in rhodopsin to an all-trans state. This changes the conformation of opsin and activates transducin (Gt) by nucleotide exchange. Gt then activates cyclic GMP phosphodiesterase to lower cyclic GMP levels and hence close cyclic-GMP-sensitive cation channels. Through a negative feedback loop, the resulting decrease in intracellular Ca2+ concentration stimulates rapid replenishment of cyclic GMP.

Which of the following represents the active form of β-catenin in cells stimulated with Wnt? A. Phosphorylated by GSK3 and CK1 B. Bound to APC C. Bound to Groucho D. Bound to LRP E. None of the above

1. Answer: E Difficulty: 2 Section: Alternative Signaling Routes in Gene Regulation Feedback: Wnt binding to Frizzled and LRP results in the disassembly of the β-catenin degradation complex (containing APC, axin, CK1, and GSK3), which allows β-catenin to accumulate and enter the nucleus, where it binds to LEF1/TCF, displacing the co-repressor Groucho.

Which of the following molecular mechanisms is NOT used in the cell in order to produce abrupt responses to a signal? A. Activation of a protein only when bound to multiple molecules of an activating ligand B. Activation of a protein only when it is phosphorylated at multiple sites C. Activation of a protein by simultaneously activating its activator(s) and inactivating its inhibitors D. A positive feedback loop in which an activated protein positively regulates its activator E. A negative feedback loop in which an activated protein inhibits its activator without delay

1. Answer: E Difficulty: 3 Section: Principles of Cell Signaling Feedback: Negative feedback generally dampens the response, while positive feedback loops and cooperative activation sharpen it.

Indicate true (T) and false (F) statements below regarding the ubiquitin ligase c-Cbl. Your answer would be a four-letter string composed of letters T and F only, e.g. TTTF. ( ) It contains an SH2 domain, and can therefore activate RTK signaling. ( ) It ubiquitylates activated RTKs. ( ) Its overactivation can lead to prolonged RTK signaling and promote the development of cancer. ( ) It is part of a negative feedback loop to down-regulate RTKs.

1. Answer: FTFT Difficulty: 2 Section: Signaling through Enzyme-Coupled Receptors Feedback: c-Cbl is a ubiquitin ligase that is recruited to activated receptor tyrosine kinases (RTKs) through its SH2 domain and inactivates the receptors in a negative feedback loop. Mutations that inactivate this feedback mechanism cause prolonged RTK signaling and can promote the development of cancer.

Intracellular Ca2+ oscillations, initiated by the activation of IP3 receptors and orchestrated via intricate positive and negative feedback loops, can be subject to frequency modulation, an example of which is the increase in oscillation frequency with increasing stimulus strength. Caffeine is known to bind to and sensitize the ryanodine receptors, resulting in their opening in response to lower calcium ion concentrations. Do you think caffeine would tend to increase (I) or decrease (D) the frequency of calcium ion oscillations in stimulated cells? Write down I or D as your answer.

1. Answer: I Difficulty: 3 Section: Signaling through G-Protein-Coupled Receptors Feedback: The effect of channel sensitization to Ca2+ is comparable to that of increased Ca2+ concentration, i.e. higher-frequency oscillations. The frequency as well as the amplitude of the Ca2+ spikes can also be modulated by other mechanisms.

Indicate true (T) and false (F) statements below regarding G-protein-coupled receptors (GPCRs). Your answer would be a five-letter string composed of letters T and F only, e.g. TTFFF. ( ) All GPCRs share a similar structure composed of seven transmembrane helices. ( ) All GPCR ligands (signal molecules) have a similar structure. ( ) GPCRs have only been found in multicellular organisms, consistent with their role in intercellular signaling. ( ) The hormone insulin is recognized by a GPCR on the surface of its target cells. ( ) Once activated, a GPCR molecule can activate multiple molecules of G protein to amplify the incoming signal.

1. Answer: TFFFT Difficulty: 1 Section: Signaling through G-Protein-Coupled Receptors Feedback: All GPCRs (found in multicellular as well as unicellular organisms) belong to a large family of proteins that share a similar structure with seven transmembrane helices. Despite this similarity, they recognize a wide variety of ligands. The GPCR activates the α subunit of a trimeric G protein, which is then released; this is usually followed by the binding of another α subunit to repeat the cycle for as long as the receptor is activated. Insulin is recognized by a receptor tyrosine kinase.

Indicate true (T) and false (F) statements below regarding cellular signaling mediated by nitric oxide (NO). Your answer would be a four-letter string composed of letters T and F only, e.g. TTTF. ( ) Once produced, NO can diffuse to neighboring cells. ( ) NO has known roles in cGMP-independent as well as cGMP-dependent signaling. ( ) NO normally decreases cGMP concentration by activating cGMP phosphodiesterase. ( ) The drug Viagra® counteracts the effects of NO on penile blood vessels.

1. Answer: TTFF Difficulty: 2 Section: Signaling through G-Protein-Coupled Receptors Feedback: Dissolved NO passes readily across cell membranes and can diffuse from its site of production to neighboring smooth muscle cells, where it increases cyclic GMP concentration by activating guanylyl cyclase. The drug Viagra® and its relatives inhibit cyclic GMP phosphodiesterase in the penis, allowing the effects of NO to last longer. NO can also signal cells independently of cyclic GMP.

Indicate true (T) and false (F) statements below regarding the mTOR complexes. Your answer would be a four-letter string composed of letters T and F only, e.g. TTTF. ( ) mTOR in complex 1 contains the protein raptor, is sensitive to rapamycin, and stimulates cell growth. ( ) Akt activation is stimulated by mTOR in complex 2, which contains the protein rictor. ( ) Akt activates mTOR in complex 2 by activating a Rheb-GAP called Tsc2. ( ) mTOR in complex 1 is activated in the presence of growth factors.

1. Answer: TTFT Difficulty: 2 Section: Signaling through Enzyme-Coupled Receptors Feedback: mTOR complex 1 is rapamycin-sensitive, and is activated in the presence of growth factors, mainly via the PI-3-kinase-Akt pathway, to stimulate cell growth. Akt phosphorylates and inhibits Tsc2, a Rheb-GAP. This activates Rheb, which then activates mTOR in complex 1.

Indicate whether each of the following descriptions applies to visual signal transduction (V), olfactory signal transduction (O), or both (B). Your answer would be a four-letter string composed of letters V, O, and B only, e.g. VOVV. ( ) It involves cGMP as a second messenger . ( ) A rise in cyclic mononucleotide concentration follows the arrival of the signal. ( ) The signal is received by a G-protein-coupled receptor. ( ) An incoming signal leads to membrane hyperpolarization.

1. Answer: VOBV Difficulty: 2 Section: Signaling through G-Protein-Coupled Receptors Feedback: Both smell and vision depend on G-protein-coupled receptors (GPCR) that egulate ion channels. Stimulation of olfactory receptors results in the opening of cyclic-AMP-gated cation channels (through the activation of Golf) and membrane depolarization in the neuron. In vertebrate photoreceptors, in contrast, GPCR activation hyperpolarizes the cell: it closes cyclic-GMP-sensitive cation channels through the activation cyclic GMP phosphodiesterase by Gt.

Fill in the blank in the following paragraph. "Cytosolic Ca2+ can be sensed by ..., a small, conserved, dumbbell-shaped protein with four Ca2+-binding sites. Upon Ca2+ binding, it binds and activates dozens of proteins by changing its conformation in different ways."

1. Answer: calmodulin Difficulty: 1 Section: Signaling through G-Protein-Coupled Receptors Feedback: Calmodulin is an important Ca2+-binding protein that helps mediate many cellular responses to Ca2+signals.

All nuclear receptors ... A. are cytosolic proteins that enter the nucleus upon ligand binding. B. have ligand-binding and DNA-binding domains, and can directly bind to DNA. C. are transcriptional activators when bound to their ligand. D. bind to steroid hormones. E. are transcriptional repressors in the absence of their ligand.

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