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Spring 2023 > PSIO 404 Exam 3 > Flashcards

PSIO 404 Exam 3 Flashcards

1
Q

Very briefly discuss the importance of heptahelical receptors.

A

heptahelical receptors are 95% GPCR but no all of them.
There are some were the N terminus faces the inside of the cell (this is abnormal)
-most abundant receptor type, encoded by one of the largest gene families
-best known are GPCRs which act as GEF (GDP-GTP exchange factor) involved in practically every aspect of cell life

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2
Q

Briefly discuss the general structures of heptahelical receptors.

A

GPCR-
seven transmembrane domains that offers nearly unlimited variability to adjust to any possible shape of signal molecules where bulky ligands bind to extracellular loops

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3
Q

Discuss the principle of multiple receptors as it applies to GPCRs.

A

a particular GPCR in the membrane gives you a coupling to a particular G protein and also the same particular protein in the membrane and through a series of modifications varying which kind of G protein it can couple with

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4
Q

Discuss the principle of variable G-protein coupling.

A

by their effectors, second messengers are able to control variable G-protein coupling
like built on negative feedback

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5
Q

Describe the activation of rhodopsin by light.

A

rhodopsin binds 11-cis-retinal unit it is converted by light into 11-trans-retinal which breaks a salt bridge between transmembrane helices 3 and 7 as it is formed, this separation of helices 3 and 7 permits the binding of Galpha subunit of transducin (the G protein coupled to rhodopsin) which then stimulated PDE6 degrades cGMP and cause hyperpolarization of the rod or cone which all the transmission of light into the brain

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6
Q

Describe some structural/functional characteristics of rod cells.

A

within the outer segment of the rod cell disc there are rhodopsin proteins
rod cells only tell you if there is light or not and and cones tell you the shades of color
rod cells are high sensitive can detect 1 photon or a million photons

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7
Q

Explain four benefits of GPCR oligomerization.

A
  1. noise filtering
  2. alteration of ligand specificity
  3. alternation ligand sensitivity
  4. alternation of receptor function
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8
Q

Discuss β-adrenergic signaling in skeletal muscle.

A

when noradrenaline binds to B2 receptor, which stimulates g protein coupling (Gs), which activates adenylate cyclase which activates cAMP production which activates PKA. PKA inhibits glycogen synthase but it also promotes the activity of glycogen and phosphorylase kinase. phosphorylase kinase promotes glycogenolysis which promotes glycogen release. But in order for phosphorylase kinase to be activated it also needs calmodulin which gets activated through calcium

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9
Q

Discuss the effect of voluntary muscle contraction on glucose release in skeletal muscles.

A

when acetylcholine binds to a nicotinic receptor this leads to calcium entry or calcium to increase within the cell which is needed for voluntary muscle contraction. This calcium can be used to activate calmodulin which can now activate phosphorylase kinase leading to the release og glucose

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10
Q

Discuss β-adrenergic signaling in adipocytes.

A

when noradrenaline binds to beta 3 and it activates the alpha subunit of the stimulatory g protein this activates adenylate cyclase which activates cAMP production which will activate PKA. PKA will inhibit perilipin and protimote lipase. lipase promotes lipolysis which promotes fatty acid release into the bloodstream.

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11
Q

Discuss α-adrenergic signaling in vascular smooth muscle.

A

when noradrenaline bind to alpha 1 receptor and activates of g protein of the q11 subfamily. This activates phospholipase C which leads to the break down of PIP2 into InsP3 and DAG. InsP3 diffused into the cytoplasm when it binds to smooth ER and cause calcium release and DAG is set free into membrane where it activates protein kinase C. From the calcium released this activates myosin light chain kinase which activates actomyosin complex which lead to contraction and blood pressure to rise

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12
Q

Discuss negative-feedback α-adrenergic signaling in sympathetic neurons.

A

when noradrenaline binds to alpha 2 receptor and activates the g i,o proteins, this causes 2 things to happen. the inhibition of ca channel and adrenylate cyclase and the promotion of k channel. The opening the potassium channel cause hyperpolarization to the neuron. the inhibition of the ca channel and adenylate cyclase prevents cAMP production which normally activated ca channels which decreased contraction for blood pressure falls

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13
Q

Describe the evoking of sympathetic effects via ACh muscarinic receptors and their associated G-protein families.

A

Gq,11 = M1,M3,M5 which promote smooth muscle contraction (lung, intestine, pupil) non viscous saliva and secretion of gastric acid and digestive enzymes
Gi,o = M2,M4 which promote through inhibition smooth muscle relaxation and decrease heart rate

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14
Q

Explain the integration of β-adrenergic and ACh muscarinic receptors in cardiac pacemaker cells.

A

since we know when noradrenaline bind to beta 2 receptor (through the sympathetic) this activates g stimulatory protein activating the production of cAMP which promotes the opening of HCN channel leading to increase in HR. When acetylcholine binds to the m2 receptor (through parasympathetic) this activates g inhibitory family which stimulates the opening of k channels and inhibits the production of cAMP leading to the closure of HCN channels and lowering HR. The cell will do whatever signal is greater, if the signals are the same the cell will not change activiy

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15
Q

Discuss PAR function as an example of a protease switch: how it is both expensive and highly effective in terms of signaling.

A

since protease activated receptor (PAR) activation is irreversible it is expensive but extremely effective

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16
Q

What does “G-protein promiscuity” mean?

A

g protein promiscuity means that it can bind to multiple g protein coupled receptors, Gq, Gi,o, and G12,13 proteins

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17
Q

Discuss 3 principles of GPCR adaptation to overstimulation.

A
  1. desensitization - within seconds of becoming activated, receptors become desensitized
  2. internalization and sequestration - desensitized receptors are internalized and sequester
  3. recycling or downregulation - sequestered receptors are either recycled back to the membrane or destroyed by proteolysis in lysosomes
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18
Q

Describe the typical life cycle of a transmembrane receptor

A

through the rough ER and golgi transmembrane receptors can be created and then through exocytotic vesicles lead them out of the cells and through exocytosis out of the cell, then old transmembrane receptors through endocytosis are brought back into the cell and brought to endosomes where they can be destroyed through lysosomes or recycled back to the golgi and rough ER

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19
Q

Describe in depth desensitization of GPCRs.

A

a strong input signal leads to desensitization of GPCR within seconds
- GPCRS are phosphorylated by a GPCR kinase (GRK) or a downstream kinase (like PKA) and uncouples the receptors from the g -proteins
-a desensited GPCR will be bound by an arrestin protein (an arrenstin takes the place of the g protein) making it an arrestin coupled signal
-an arrestin also induces internalization of the receptor
*arrestin coupled signaling can occur anytime arrestin is bound especially before internalization

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20
Q

Describe in depth internalization and sequestration of GPCRs.

A

now that GPCR are bound to arrestin, this allows for clathrin to also bind and this causes a pit to form in the membrane. When this clathrin coated pit, there are desensitized receptors. Arf6, ARNO, AP2, clathrin, and arrestin are all bound to this GPCR this all for dynmin to begin to for a ring and bing to pinch off the vesicle and become an endosome. This endocytotic vesicle can be delivered to the lysosomes and become destroyed or can be sequestered and returned to the plasma membrane

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21
Q

Describe in depth recycling or downregulation of GPCRs.

A

so if the receptors become sequestered then two things can happen
1. they can be destroyed by lysosomes through downregulation (down-modulation)
2. they can be recycled through the golgi apparatus back to the plasma membrane no longer desensitized
-a cell has to go through a recovery phase to become resensitized
-this is made possible by dephosphorylation of GPCR by a GPCR specific phosphatase (PP2A)
-then an exocytotic recycling vesicle will bring the GPCR back to the membrane
-this can only be done with a short term overstimulation long term gets destroyed

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22
Q

Describe β-adrenergic signaling as an example of GPCR adaptation, and identify the level of adaptation which involves MAO & COMT DO not do this one

A

this can happen at two levels
1. extinction of the input signal by dilution (synaptic re uptake) or by metabolic inactivation thanks to enzymes like COMT or MAO
-COMT and MAO modify norepinephrine to make it less able to activate the receptor

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23
Q

Discuss the amplification of a signal (the extreme sensitivity) which occurs in a rod cell when it detects a photon, and explain the need for adaptation by rod cells

A
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24
Q

Briefly discuss the two criteria which determine maximal receptor performance.

A
  1. adaption - which allows us to be as sensitive as possible
  2. rapid temporal discrimination - which all the rod cells to process the arrival of a photon to change their activity and then rest and be ready for the nest photon within 150 microseconds
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25
Discuss the goal of adaptation of rhodopsin to light.
the goal is to respond with maximal sensitivity over a range of signal intensities -this range has to appropriate for bright light and a dark light and the ability for the photoreceptors to be able to adaptive to both
26
Discuss in detail the adaptation of rhodopsin to light in rod cells.
in bright light : 1. photon activates rhodopsin 2. rhodopsin activates up to 500 gt-proteins 3.rhodopsin kinase desensitizes rhodopsin by phosphorylation 4.desensitized rhodopsin binds arrestin makes the rod less sensitive in low light : 5. constitutively active phosphatase eventually re activate rhodopsin so the rod is more sensitive to light now 6.calcium levels rise in the dark leading to inhibition of rhodopsin kinase which make for a more and more dark adapted light sensitive state fully adapted after about 2 hours
27
Protease activated receptors (PARs) do not couple with G-proteins of which major subfamily? G12,13 Gq,11 Gs Gi,0
Gs
28
Protease activated receptors (PARs) do not couple with G-proteins of which major subfamily? G12,13 Gq,11 Gs Gi,0
Gs
29
When a ligand binds and activates a GPCR, second messengers can be generated as a result. Often times, those second messengers activate enzymes that make modifications to the upstream GPCR in addition to other targets. If the upstream GPCR is modified in a way that allows it to interact with a different family of G-proteins, it is an example of which principle? the principle of variable G-protein coupling the principle of noise filtering the principle of adaptation the principle of multiple receptors
the principle of variable G-protein coupling
30
α1-adrenergic receptors are coupled with G-proteins of which subfamily? Gq,11 Gi,0 Gs G12,13
Gq,11
31
α2-adrenergic receptors are coupled with G-proteins of which subfamily? Gi,0 G12,13 Gs Gq,11
Gi,0
32
α2-adrenergic receptors are coupled with G-proteins of which subfamily? Gi,0 G12,13 Gs Gq,11
Gi,0
33
M1, M3 and M5 receptors are coupled with G-proteins of which subfamily? G12,13 Gq,11 Gi,0 Gs
Gq,11
34
Detection and processing of light by rod cells begins with the conversion of __________ into __________ by a photon of light. 11-cis-retinal; 11-trans-retinal transducin; rhodopsin 11-trans-retinal; 11-cis-retinal rhodopsin; transducin
11-cis-retinal; 11-trans-retinal
35
which major family of G-proteins does not activate an enzyme that acts on PIP2? the Gs family the Gi,0 family the Gq,11 family
the Gs family
36
Which of the following is not a benefit of GPCR oligomerization? redundancy alteration of receptor function alteration of ligand specificity alteration of ligand sensitivity
redundancy
37
Which protein was discussed in lecture as being activated by the presence of calcium in the cytoplasm (sarcoplasm) of a skeletal muscle cell? glycogen synthase calmodulin PKA adenylate cyclase
calmodulin
38
M2 and M4 receptors are coupled with G-proteins of which subfamily? Gq,11 G12,13 Gi,0 Gs
Gi,0
39
Discuss some basic principles of cell sensation via protein kinase (PK)-coupled receptors. Explain the difference between intrinsic and associated kinase activity.
1. principles of signaling via protein kinase coupled receptors -receptors are activated by ligand induced oligomerization, usually dimerization, and the resulting trans-autophorylation of kinase domains 2.protein kinase coupled receptors with intrinsic Ser/Thr kinase activity (TGFbeta) 2. protein kinase coupled receptors with associated Ser/Thr kinase activity (cytokine receptors like TNF alpha, IL-1 and Toll receptors)
40
Rank the types of PK-coupled receptors by complexity, by use in the DPPN of animals, and by intrinsic vs. associated kinase activity.
most complex 1. tyrosine -specific 2. serine/threonine specific 3. histidine - specific less complex
41
Describe the general mode of action of a PK-coupled receptor
a signal binds to one or all receptors monomers which causes oligomerization, typically dimerization, which facilitates the activation of the kinase domain. this activation begin additional modifications to the receptor monomers and this continues to create signaling complex allowing for proteins to be modified, phosphorylated and recruited which leads to the progression signalling pathways until things need to come to an end by dephosphorylated the receptor
42
Discuss the critical importance of TGFβ (a PK-coupled receptor with intrinsic Ser/Thr kinase activity in animals)
tgfb is essential for tissue development and tissue maintenance -it is a multifunction tissue hormone that regulates many physiological functions from embryogenesis to wound healing
43
Describe the mechanism of signaling by TGFβ receptors, including the role of SMADs in the pathway **
there are three receptor types that exist but TGFB only bind to type 1 and type 2, type 2 are constitutively active. when type 1 is phosphorylated, they phosphorylate R-SMADS -R-SMADS are transcription factors which translocate to the nucleus upen heterodimerization with a Co-SMAD -
44
Discuss the use of PK-coupled receptors with associated Ser/Thr kinase activity by human cells, including their role in processing immune system signals
these are used to sense cytokines which control innate and adaptive immunity and are used for communion between them -Ser/Thr kinase coupled cytokines receptors sense messages controlling innate immunity
45
Describe some general characteristics of family III & IV cytokine receptors.
-ligans (cytokine) binding exposed interaction domains -interaction domain connect to adapter proteins which stimulate apoptosis and or immunomodulatory and proinflammatory signaling through NFkB modules or MAP kinase modules leading to defense responses
46
Describe the design of NFκB modules, and explain how they are triggered by family III cytokine receptors.
they process signals that control innate and acquired immune defense they have three components 1. protein kinase For an NFκB module, the component or subunit is the input-sensitive portion 2. regulatory subunit -freed from inhibition, For an NFκB module, the component or subunit can be modified in such a way that it is "primed" for degradation 3. catalytic subunit For an NFκB module, the component or subunit can be released from inhibition to act as a transcription factor
47
Describe the design of MAP Kinase modules and explain how they are triggered by family III cytokine receptors
consist of 3 kinases connected in series they produce transcription factors BUT they are not transcription factors 1. MAP3K -inputs activate MAP3K and they phosphorylation of two serine residues 2. MAP2K dual phosphorylation of Thr-X-Tyr sequence 3. MAPK -lead to output signals like metabolism, gene transcription and mobility *MAP2K and MAPK are highly specific
48
Discuss in detail TNFα signaling by family III cytokine receptors
TNFa is a tumor nectrosis facor has immunomodulatory effects on cells and causes tumor death by apoptosis -it is expressed as a homotrimeric transmembrane protein on the surface of leukocytes and lymphocytes but it can also be shed by membrane bound proteases 0the strongest endogenous trggiers of apoptosis are found within the TNF family of cytokines SIGNALING PATHWAY: when TNFa binds to TNFR1 or to TNF2 (on the surface of white blood cells). when it binds to TNFR! it leads to interaction of death domains which enables the association of TRADD. TRADD can lead to the activation of FADD RIPK1 and 3, and TRAF2 *FADD = apoptosis *RIPK1 & 3 = necrosis *TRAF2 = auto-ubiquitylation
49
Discuss in detail IL1 signaling by family IV cytokine receptors.
the cytokine IL-1 is the endogenous coordinator of innate immunity defense reaction -the is sensed by IL1R ILR has extracellular interleukin binding IL1 domains necessary for binding IL1. IL1R contains TIR domains, MyD88, that recruit proteins with the same kind of domain which then cause the formation of this signaling complex. MyD88 bind IRAK1 and IRAK4, IRAK1 and IRAK4 are Ser/Thr specific kinases that become phosporated and the IRAKE 1 is released from IRAK4 and able to interact with TRAF 6 with then auto ubiquitylation and activates adaptor proteins that activate NFkB and MAPK to lead to proinflammatory mediators
50
Discuss in detail signaling by Toll-like receptors: their ligands (LPS and lipoteichoic acid) and mechanisms of signal transduction
LPS (gram neg bacteria), interact with TLR4 that interact with MyD88 which phosphorylate IRAK1 & 4 which activate TRAF6 which activates adaptor proteins that activate NFkB and MAPK to lead to proinflammatory mediators -lipoteichoic acid (gram positive bacteria)
51
Which protein contains EF-hand domains and is thus sensitive to changes in calcium concentration? recoverin rhodopsin transducin rhodopsin kinase
recoverin
52
Adaptation is one the four characteristic of high-performing data-processing systems. Which of the additional characteristics listed below is not one of the four? redundancy noise filtering pattern generation tolerance
tolerance
53
What structural protein forms basket-like aggregates to stabilize invaginations of the plasma membrane during the process of endocytosis? arrestin dynamin COMT clathrin
clathrin
54
Which step of cellular receptor adaptation does not require the binding of arrestin? GPCR recycing GPCR desensitization GPCR down modulation GPCR internalization and sequestration
GPCR desensitization
55
Which of the following is not a protein which can desensitize a GPCR? MAO GRK PKA PKC
MAO
56
Identify the light-sensitive protein of rod cells. transducin recoverin arrestin rhodopsin
rhodopsin
57
What is the term for the sequence of events following receptor over-stimulation that ends with with degradation of receptors in lysosomes? receptor transactivation internalization down-modulation β-arrestin coupling
down-modulation
58
Which of the following proteins is a small G-protein? arrestin AP2 ARNO Arf6
Arf6
58
Which of the following proteins is a small G-protein? arrestin AP2 ARNO Arf6
Arf6
59
What protein associates with a number of identical proteins to form a contractile ring during the process of endocytosis? dynamin ARNO AP2 clathrin
dynamin
60
What happens to the membrane potential of a dark-adapted rod cell when light causes the activation one or more of its rhodopsin proteins? depolarization hyperpolarization
hyperpolarization
61
For an NFκB module, which component or subunit can be released from inhibition to act as a transcription factor? the regulatory subunit the protein kinase the "catalytic" subunit
the "catalytic" subunit
62
PK-coupled receptors with associated Ser/Thr kinase activity that are activated by tumor necrosis factor (TNF) and related proteins belong to which family of cytokine receptors? Family I Family II Family III Family IV
Family III
63
PK-coupled receptors with associated Ser/Thr kinase activity that are activated by tumor necrosis factor (TNF) and related proteins belong to which family of cytokine receptors? Family I Family II Family III Family IV
Family III
64
Like other PK-coupled receptors, TGFβ receptors require dimerization for activation. However, unlike other PK-coupled receptors, activation requires heterodimerization between type II and type I receptors. Identify a major difference between the two receptor monomers. Neither type I nor type II receptors are constitutively active, but the binding of ligand leads to activation of type II receptors which are actual transducers of the signal. Neither type I nor type II receptors are constitutively active, but the binding of ligand leads to activation of type I receptors which are actual transducers of the signal. Type II receptors are constitutively active. Type I receptors are constitutively active.
Type II receptors are constitutively active.
65
For an NFκB module, which component or subunit can be modified in such a way that it is "primed" for degradation? the protein kinase the regulatory subunit the "catalytic" subunit
the regulatory subunit
66
Identify the sole example of signaling in human cells through PK-coupled receptors with intrinsic Ser/Thr kinase activity. TGFβ signaling IL-1 signaling stimulation of Toll-like receptors TNFα signaling
TGFβ signaling
67
Cellular signals which stimulate and control innate immunity bind to PK-coupled receptors with associated Ser/Thr kinase activity. Cysteine kinase activity. Tyr kinase activity. Histidine kinase activity.
Ser/Thr kinase activity.
68
PK-coupled receptors with associated Ser/Thr kinase activity that are activaed by microbial surface components belong to which family of cytokine receptors? Family I Family II Family III Family IV
Family IV
69
SMADs are human gene products which are related to Caenorhabditis elegans Sma genes and the Drosophila protein Mad, and their name is a fusion of those gene names. After ligand-induced receptor activation, R-SMAD is phosphorylated, R-SMAD/Co-SMAD dimers form, and then R-SMAD/Co/SMAD dimers act as transcription factors in the nucleus. Which combination of interactions in the nucleus is sufficient to cause repression of gene transcription? DNA + R-SMAD/Co-SMAD + Ski DNA + R-SMAD/Co-SMAD + Ski + HDAC-complex DNA + R-SMAD/Co-SMAD + CBP/P300
DNA + R-SMAD/Co-SMAD + Ski + HDAC-complex
70
SMADs are human gene products which are related to Caenorhabditis elegans Sma genes and the Drosophila protein Mad, and their name is a fusion of those gene names. After ligand-induced receptor activation, R-SMAD is phosphorylated, R-SMAD/Co-SMAD dimers form, and then R-SMAD/Co/SMAD dimers act as transcription factors in the nucleus. Which combination of interactions in the nucleus is sufficient to cause repression of gene transcription? DNA + R-SMAD/Co-SMAD + Ski DNA + R-SMAD/Co-SMAD + Ski + HDAC-complex DNA + R-SMAD/Co-SMAD + CBP/P300
DNA + R-SMAD/Co-SMAD + Ski + HDAC-complex
71
Which component of a given MAPK module is a transcription factor? the MAPK component the MAP2K component the MAP3K component None. Upon activation, MAPKs can phosphorylate transcription factors, but they are not transcription factors themselves.
None. Upon activation, MAPKs can phosphorylate transcription factors, but they are not transcription factors themselves.
72
Which component of a given MAPK module is a transcription factor? the MAPK component the MAP2K component the MAP3K component None. Upon activation, MAPKs can phosphorylate transcription factors, but they are not transcription factors themselves.
None. Upon activation, MAPKs can phosphorylate transcription factors, but they are not transcription factors themselves.
73
For an NFκB module, which component or subunit is the input-sensitive portion? the "catalytic" subunit the protein kinase the regulatory subunit
the protein kinase
74
Explain the roles that RTKs play in animals, including a description of their typical ligands and the common structural features shared by RTKs.
-there mechanism of cellular sensation is more universal than cellular sensation via GPCR -receptors are activated by 1. ligand induced oligomerization (usually dimerization) 2. the resulting trans autophosphorylation of kinase domains -receptors have either intrinsic kinase domain or docking domain for sperare kinases -output kinases are either Ser/Thr specific or Tyr-specific
75
Briefly describe the mode of action of RTKs.
1. dimerization 2. trans autophosphorylation results in full activation of RTK kinase domains so 2. recruitment can happen
76
Discuss the initiation of RTK signaling via redox signaling, and discuss the termination of RTK signaling via phosphatase action
Initiation: - ligand induced activation of RTKs leads to PI3K mediated activation of Rac, which then switches on the production of ROS from NADPH -ROS inactivates protein tyrosine phosphatase (PTP) preserving RTK signaling termination: -the temporary increase in ROS is reversed and this is accompanied by recovery of PTP enzymatic activity -re-activated PTP enzymatic activity leads to RTK dephosphorylation and to the termination of downstream RTK signaling
77
Discuss in detail the principle of RTK adaptation (desensitization, internalization, and down-regulation), and explain the critical role played by Cbl-type proteins
upon prolonged stimulation, RTKs become internalized and can be destroyed inside the cell in lysosomes OR be recycled back to the membrane -one of the signals for internalization is mono ubiquitinyation by E3 ubiquitin ligase (Cbl) 1. ligand induced dimerization for activation 2. trans autophosphorylation for activation / stabilization 3. recruitment of substrate (signaling proteins)
78
Describe the functions of SH2 and SH3 domains through the example of Src activation/deactivation via phosphorylation
*SH2 binds phospho-Tyr *RING bind E2 ubiquitin-conjgating enzymes -SH2 domains help form sigaling complexes and also regulate a protein structure -Src activation require 1. changes in the interaction of SH2 and SH3 domains 2. specific dephosphorylation by other proteins 3. autophospohoryaltin of the activation loop
79
Regarding intrinsic RTK signaling via adaptor proteins (including IRSs), explain how this illustrates redundancy and amplification ***
-insulin binding recruits many docking proteins to influence many effector proteins -best known for insulin receptor substrate (IRS) *Clb is an IRS -this illustrates redundancy because -this illustrates amplification because
80
Describe in detail insulin signaling in cells: glucose absorption, glycogen synthesis, and receptor inhibition via feedback
↑ uptake of Glucose by GluT4 transport – via activated Insulin Receptor (IR) → IRS → PI3K → PIP3 → PDK1 → PKB/Akt (—| AS160 —| Rab) → fusion of GluT4- containing vesicles to the plasma membrane ↑ glycogenesis – via activated Insulin Receptor (IR) → IRS → PI3K → PIP3 → PDK1 → PKB/Akt —| GSK3 —| glycogen synthase (GS) ↓ gluconeogenesis – via Shc → Grb2 → Ras → RAF → MEK → ERK —| transcription of gluconeogenesis genes
81
Describe bi-directional signaling as illustrated through ephrin signaling, including the role/targets of ephrin signaling via PDZ domains
* Increased targeted growth processes such as axonal guidance or angiogenesis 1. via attraction: B-ephrins bind with ephrin receptors → Tyr kinases → PDZ interactions → activation/recruitment of scaffold proteins (syntenin), motor proteins (dynamin), and cytoskeleton-modifying proteins (Cdc42/Rac). 2. via repulsion: B-ephrins do not bind with ephrin receptors
82
Briefly discuss the general mechanisms and targets of FGF signaling. Also, be able to identify genetic diseases of the single FGF receptor by name.
-consitutley active FGF binding stimulates multiple signaling pathways, including 1. The PI3K-PKB/Akt Pathway (survival) 2. The Ras-MAPK Pathway (proliferation, differentiation) 3. The PLC-PKC Pathway (movement) * Increased survival via PI3K → PIP3 → PDK1 → PKB/Akt pathway —| apoptosis * Increased growth/differentiation via Grb2 → Ras → RAF → MEK → ERK module * Increased migration/reorganization via PLCgamma->DAG/InsP3 → PKC pathway Genetic mutations: Crouzon syndrome = too long of skull Apert syndrome = no separation of digits Achondroplasia = disproportionate growth but without the severe malformation (when long bones with growth plate fuse to early)
83
Describe heparan sulfate and the purpose that is served by the requirement for its binding to the FGF receptor (Hint: heparan sulfate must be present to assure proper epithelial repair after a deep cut)
* There is only one FGF receptor, and there are only 4 isoforms. * Each disorder is due to a point mutation in the FGF receptor gene which causes overactivation * Interestingly, the FGF receptor also needs to bind heparan sulfate (an extracellular matrix component) to become activated
84
Discuss the association and actions of JAK Tyr kinases.
* Family I & II cytokine receptors associate with Tyr kinases of the JAK (Janus Kinase) family – Upon transautophosphorylation, JAKs activate downstream pathways like RTKs do (MAPK modules, etc.). – Major substrates of JAKs that transmit signals to the nucleus are transcription factors of the STAT family. * STATs form homo- or heterodimers upon phosphorylation by JAKs which then translocate to the nucleus. * STAT transcription factors bind to g-interferon activation sequence response elements in the genome
85
Describe the function of STATs and SOCS.
STAT signaling is inhibited by negative feedback. For example, STATs induce expression of suppressors of cytokine signaling (SOCS) which block the catalytic domain of JAKs and trigger ubiquitinylation of the associated cytokine receptor.
86
Discuss in detail signal transduction via the JAK-STAT pathway for the IL2 receptor
1. IL-2 Signaling Summary * Costimulation/triggering of immune system responses via IL-2R → JAK → STAT → transcription of genes with “gamma- interferon activation sequence” response elements
87
Briefly describe T cell activation and T cell co-stimulation?
-activation begins with recognition of antigen displayed by MCH1 or MCH 2 proteins -With co-stimulation, T cells become activated, then they: – Enlarge, proliferate, form many genetically-identical copies – Some daughters are backup (memory cells) – Other daughters differentiate to perform functions specific to T cell type (T helper in this case) * Effector T helper cells enable both cell-mediated and antibody-mediated immunity
88
Briefly describe the structure and function of MHC I and II, the T cell receptor, and their interaction
-MHC I presents endogenous antigen (pieces of protein found inside of our cells) and has one transmembrane domain (cytoplasm) * MHC II presents exogenous antigen (pieces of protein found outside of our cells) and has two transmembrane domains (from floating outside) * Each T-cell expresses thousands of copies of a unique T-cell receptor, one of the 1015 possible results of gene rearrangements. * Rearrangement of a and b genes leads to unique binding sites every time a new T cell develops in the bone marrow. * Every newborn T-cell has a unique TCR gene
89
Discuss in detail signal transduction by TCRs binding antigen
The TCR is formed from six different transmembrane proteins: subunits a, b, g, d, e, and z. * Subunits a & b form the variable region while other subunits have ITAM (Immune receptor Tyrosine Activation Motif) sequences which have two Tyrosines each. * Once phosphorylated by the associated Tyr-kinase, ITAMs recruit SH2- and PTB- containing proteins like ZAP70 (Zeta-chain Associated Protein Kinase of 70 kDa) which propagate and amplify the signal. -CD28 (on Th) -CD80/86(on APC) initiates binding In the case of prolonged binding: 1. MHCII-antigen-TCR complex with CD4 recruits multiple proteins to the contact site 2. CD45 is characteristic for blood cells (all but RBCs), and it interacts w/ proteins like CD22 on B-cells. * This would occur largely where cell-cell contact is happening between a TH cell and a B cell. * This way, CD45 can activate Lck, the associated Try kinase 3. CD45 activates Lck which phosphorylates ITAM sequences. 4. ZAP70 phosphorylates scaffold protein LAT. 5. LAT binds Csk which inactivates Lck. 6. LAT also activates Itk (Interleukin 2-activated Tyr- kinase) which amplifies signal, prolonging TCR-MHC binding for co-stimulation -the point is to influence IL-2 IL2 and other signals will facilitate the transitions from recognititon to activation for the lymphocytes
90
Discuss in detail the structure and function of integrins
91
Given their functions, would over-expression or under-expression of ephrins favor tumor growth? over-expression under-expression
over-expression
92
Given their functions, would over-expression or under-expression of ephrins favor tumor growth? over-expression under-expression
over-expression
93
Which interaction domain enables a protein to interact with an E2 ubiquitin ligase? PTB PH SH3 RING
RING
94
Deactivation of which protein is essential for full initiation of RTK signaling? NADPH oxidase Rac PI3K PTP
PTP
95
For active SRC, tyrosine _____ is phosphorylated, but tyrosine _____ is not phosphorylated. 416; 527 307; 416 527; 307 527; 41
416; 527
96
For active SRC, tyrosine _____ is phosphorylated, but tyrosine _____ is not phosphorylated. 416; 527 307; 416 527; 307 527; 41
416; 527
97
For the full initiation of signaling downstream of an RTK, activated _____ must trigger production of ROS by NADPH oxidase in the plasma membrane. Trx Rac PTP PTEN
Rac
98
True or False: In response to excessive stimulation, both RTKs and GPCRs can be desensitized by phosphorylation of the receptor. True False
False
99
vCbl of mice is a truncated form of Cbl that lacks the RING domain. What does this alteration do to Tyr kinase-coupled receptor signaling? Tyr kinase-coupled receptor signaling will be alternatively coupled to arrestin. Tyr kinase-coupled receptor signaling lasts a much shorter length of time than it would normally. Tyr kinase-coupled receptor signaling lasts much longer than normal. Tyr kinase-coupled receptor signaling is unaffected.
Tyr kinase-coupled receptor signaling lasts much longer than normal.
100
Which example of RTK signaling requires interaction with both its ligand and the extracellular matrix for successful initiation? ephrin signaling insulin signaling FGF signaling
FGF signaling
101
Which example of RTK signaling requires interaction with both its ligand and the extracellular matrix for successful initiation? ephrin signaling insulin signaling FGF signaling
FGF signaling
102
Which signaling pathways involve bi-directional signaling, engaging associated Tyr kinase activity in one cell while simultaneously engaging Tyr kinase-coupled receptors with intrinsic kinase activity in the other cell? FGF signaling pathways ephrin signaling pathways insulin signaling pathways
ephrin signaling pathways
103
Which signaling pathways involve bi-directional signaling, engaging associated Tyr kinase activity in one cell while simultaneously engaging Tyr kinase-coupled receptors with intrinsic kinase activity in the other cell? FGF signaling pathways ephrin signaling pathways insulin signaling pathways
ephrin signaling pathways
104
Place the following steps of cellular adaptation to excessive signaling in order. ___ desensitization ___ internalization ____ recycling or down-modulation ____ sequestration
1. desensitization 2. internalization 3. sequestration 4. recycling or down-modulation
105
Identify an appropriate downstream target protein for the activated JAK enzyme. STAT TRAF2 FAK a protein with ITAM sequences
STAT
106
Identify an appropriate downstream target protein for the activated JAK enzyme. STAT TRAF2 FAK a protein with ITAM sequences
STAT
107
Identify an appropriate downstream target protein for the activated Lck enzyme. FAK STAT a protein with ITAM sequences TRAF2
a protein with ITAM sequences
108
In order to be activated, Lck (like other members of the Src family of kinases) must be dephosphorylated at a particular residue. Identify the enzyme which activates Lck when a T-cell receptor recognizes antigen presented by MHC II. CD45 CD4 CD22 CD28
CD45
109
For a T-Cell Receptor found on a T cell in circulation or in secondary lymphatic organs and tissues such as lymph nodes, which subunits contain variable proteins sequences (the result of genetic recombination)? subunits δ and ε subunits ε and ζ subunits γ and δ subunits α and β
subunits α and β
110
For the following examples of RTKs with associated Tyr kinase activity, match the appropriate associated Tyr kinase with the receptor type given. 1. the T-cell receptors (TCR) 2. the IL2 receptor 3. receptors of the extracellular matrix (integrins) ____ focal adhesions-associated kinases (FAKs) ____ a member of the Src family of kinases (Lck) ____ Janus kinases (JAKs)
__3__ focal adhesions-associated kinases (FAKs) __1__ a member of the Src family of kinases (Lck) __2__ Janus kinases (JAKs)
111
For the sake of our discussion, MHC I presents fragments of proteins to TCRs on which type of T cells? TC cells TH cells
TC cells
112
Which of the following statements about the interleukin 2 receptor is false? STAT proteins are recruited to the activated receptor by means of their Group 2 interaction domains (domains such as SH2 and PTB) for phosphorylated tyrosine. After it is activated, the receptor itself is phosphorylated by activated JAK. It is a dimer. When activated, it induces trans-autophosphorylation of JAK.
It is a dimer.
113
Which sequence in DNA is the binding target of activated STAT proteins (STAT dimers)? the phenobarbitol response element the γ-interferon activation sequence response element the cAMP response element the dioxin response element
the γ-interferon activation sequence response element

Spring 2023 (7 decks)

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