Chapter 18 Flashcards
1
Q
Cells express receptors in order to?
A
respond to signals in their environment
2
Q
The cell receptors receive the signal and convey the information to intracellular targets via
A
signal transduction
3
Q
5 categories of signaling
A
a. neurotransmitter (synaptic)
b. endocrine
c. paracrine
d. autocrine
e. contact-dependent
4
Q
What are 8 general classes of proteins/mechanisms involved in signal transduction?
A
a. G protein-coupled receptors
b. receptor protein kinase
c. phosphoprotein phosphatases
d. guanylyl cyclase
e. ion channel receptors
f. two-component system
g. transmembrane scaffolds
e. nuclear receptors/transcription factors
5
Q
G protein-coupled receptors are linked to
A
trimeric GTP-binding proteins
6
Q
Function of receptor protein kinases
A
phosphorylate their intracellular substrates
7
Q
Function of phosphoprotein phosphatases
A
dephosphorylate substates
8
Q
Function of guanylyl cyclase
A
catalyzes the GTP to 3’-5’ cyclic GMP
9
Q
Function of ion channel receptors
A
change their conformation to permit ion flux through a pore
10
Q
What are the 2-component system?
A
a sensor + a response regulator
11
Q
Function of transmembrane scaffolds
A
help recruit regulatory proteins to a site on the membrane
12
Q
Most cell-sensed signals are _____
A
chemical
13
Q
What are 4 receptors that can respond directly to physical inputs?
A
a. pressure-sensing channels
b. mechanical strain sensors
c. electrical field sensing channels
d. heat/pain sensing o ion channels
14
Q
Two functional domains in receptors
A
a. ligand-binding domain
b. effector domain
15
Q
How can a cell control its responsiveness to an extracellular signal? (3)
A
a. by regulating the synthesis of a receptor
b. by regulating the degradation of a receptor
c. by regulating the receptor’s activity
16
Q
Multiple different ligands can bind to receptors of the same class, generating _____ response
A
similar intracellular
17
Q
A ligand may bind to more than one kind of receptor, eliciting _____ response.
A
more than one type of
18
Q
Two domains of receptors allow the cell to regulate
A
the binding of ligand and the effect of ligand independently
19
Q
Covalent modification or allosteric regulation can change what two?
A
change ligand-binding affinity or the ability of the ligand-bound receptor to generate its signal; or both
20
Q
Some receptors have _____ activity
A
catalytic
21
Q
Most receptors use small energy of ligand binding to do what?
A
accelerate reactions driven by other energy sources
22
Q
Most signaling events change ____
A
reaction rates
23
Q
What is an important function of receptors that occur at several steps along the second messenger pathways?
A
molecular amplification
24
Q
Various molecular conformations of receptors can be shifted from one to another via ___
A
ligand binding
25
What are nearly inactive in the absence of ligand?
physiological receptors
26
Most receptors are less than 1% active if _______
without agonist
27
Some ligands that only promote submaximal activation of their receptor
partial agonists
28
What is a competitive inhibitor that binds to a ligand's binding site?
antagonist
29
Function of antagonist
prevents the activating ligand from binding
30
What is a ligand that binds preferentially to the inactive conformation of the receptor?
inverse agonist
31
Inverse agonist binding to the inactive conformation of the receptor causes what?
net inhibition by shifting the conformational equilibrium to the inactive site
32
What are the 2 branching of the signaling pathways?
divergent branching and convergent branching
33
What does divergent branching allow?
linked control from one receptor to more than one process
34
What does convergent brancing allow?
several receptors to activate the same pathway to elicit the same regulatory responses
35
_____ within cells created by overlapping converging and diverging singlinag pathways allow for the ______ of responses to multiple inputs
singlaing networks; coordination
36
What are signaling networks that include components in various subcellular locations?
spatially complex
37
What is the circuit with OR, AND, or NOT functions?
Boolean logical circuits
38
What is the quantitative interactions between converging signals of A or B function?
additive
39
What is the quantitative interactions between converging signals of A AND B function?
More than additive
40
What is the quantitative interactions between converging signals of A NOT B function?
less than additive
41
Positive feedback loops
irreversible ON switch
42
Positive feed-forwards loop
responds to prolonged input
43
Conformational lock
dual control switch
44
Conformational lock uses what
1 input to control the reversibility of a 2nd regulatory event
45
Scaffolds binds several components of a signaling pathway in _____ to enhance _____
multiprotein complex; signaling efficiency
46
Scaffolds bind to specific proteins with what?
considerable selectivity
47
What activity does scaffolds have?
enzymatic activity
48
Scaffolds binding to several molecules needed in one loaction results in (4)
a. activation/inactivation of componens is accerleated
b. interactions of porteins that have a low affinity for each other are promoted
c. signaling porteins are localized to appropriate sites of action
d. local concentrations of the signaling components are increased
49
What is the scaffold in drosophila photoreceptor cells?
InaD
50
What is the scaffold in S. cerevisiae mating response?
Ste5p
51
Excess scaffolds may ____ because of diluting the components
inhibit signaling
52
Inhibition of signaling due to excess scaffolds result in
preventing their productive interaction
53
PKC
protein kinase C
54
PLC
phoslipase C
55
alpha and beta
heterotrimeric G-protein
56
What domains recognize a group of targets that share related structural features?
modular interaction domains
57
Apoptosis function
links 2 or more proteins
58
What is a proto-oncogene first discovered in Src?
protein tyrosine kinase proto-oncogene
59
What are the domains of protein tyrosine kinase proto-oncogene?
protein tyrosine kinase domains plus SH2 amd SH3
60
SH2
Src homology 2 domain
61
SH3
Src homology 3 domain
62
SH3 domain bind to what?
short proline-rich sequnences
63
SH3 domain bind to short proline-rich sequences present in what?
both resting and activated cells
64
SH3 domain is _____ regulated by what?
negatively; phosphorylation within the proline-rich motif
65
SH2 domain bind to what?
tyrosine phosphorylated proteins
66
SH2 domains bind to tyrosine phosphorylated proteins like
cytoplasmic tyrosine kinases and receptor tyrosine kinases
67
Adaptor proteins link to ______ and target them so they respond to _____.
signaling molecules; extraccellular signals
68
Adaptor proteins bind to ____ via what?
2 or more oher signaling proteins; protein-protein interaction domains
69
What is an example of an adaptor?
Grb2
70
Grb2 adptor has what domains?
1 SH2and 2 SH3 domains
71
Why do cells continuously adjust their sensitivity to signals?
to maintain their ability to detect changes in input
72
cells commonly regulate their sensitivity to _____ over more than a ______range
physiological stimuli; 100-fold
73
mammalian visual response adapt over a ____ range of incoming light
10^7 fold
74
What is the general mechanism for adaptation?
negative feedback loop
75
Stronger or more persistent inputs tend to drive what?
greater adaptive change and more lasting adaptation
76
What is an example of adaptation?
G protein pathways
77
What is the earliest adaptation?
receptor phosphorylation by a GRK
78
GRK
G protein-coupled receptor kinase
79
Function of GRK?
recognizes the receptor's ligand-activated conformation
80
The receptor phosphorylation inhibits what?
the ability of the receptor to stimulate G protein activation
81
The receptor phosphorylation promotes what?
binding of arrestin
82
Binding of arrestin further inhibits what?
G protein activation
83
Function of arrestin
primes receptors for endocytosis, helping to remove them from the cell surface
84
Where may the receptor be degraded?
in the endosomal/lysosome pathway
85
Degradation of receptor in the endosomal/lysosome pathway may be coupled with what?
feedback inhibition of transcription of the receptor
86
The diversity of properties of different signaling proteins are due to (3)
a. multiple genes
b. differential mRNA splicing
c. mRNA editing
87
The diversity allows cell to _____ and ______
alter how it performs otherwise identical signaling functions; have its signaling pathways remarkable resistant to mutational or other injuries
88
What can be compensated for by increased expression or activity of another species?
loss of a single species or isoform of a signaling protein
89
3 separate regulation
a. protein kinases vs. phosphoprotein phosphatases
b. adenylyl cyclase vs. phosphodiesterases or anion transporter to pump it out of the cell
c. GEFs vs. GAPs
90
Function of Adenylyl cyclase
create cAMP
91
Function of phosphodiesterases
hydrolyze cAMP
92
Function of GEFs
activate G proteins
93
Function of GAPs
deactivate G proteins
94
Most common mechanisms for regulating the activities of intracellular protein are via
allosteric interactions or covalent modifications
95
Allostery refers to a noncovalent binding of some molecule to do what?
a. to effect a change in the conformation of a target protein
b. to change the target protein's activity
96
Allostery can be reversible or irreversible?
reversible
97
Allostery can be either _____ or ______
inhibitory or stimulatory
98
____ of a target protein alters conformation and leads to its activity
covalent modifications
99
Covalent modifications are reversible or irreversible?
reversible
100
Covalent modifications can be either ____ or _____
inhibitory or stimulatory
101
What are examples of covalent modifications?
phosphorylation, dephosphorylation, methylation, acetylation, ubiquitination, glycosylation, and ribosylation
102
What are small and diffusible molecules?
second messengers
103
What are 4 advantages of small molecule?
a. synthesized and destroyed quickly
b. act at high concentrations so their affinities for target proteins can be low
c. low affinity allows rapid association, signal can be determined promptly by destruction of free second messenger
d. diffuse quickly within the cell
104
What are 2 protein advantages?
a. catalytic activity
b. able to bind multiple molecules simultaneously
105
Second messenger examples of modified nucleotides
cAMP, cGMP, cADP-ribose
106
second messenger examples of sugar phosphate
IP3 (inositol-14,5-triphosphate)
107
Second messenger example of divalent metal ion
Ca2+
108
Second messenger example of gasses
NO (nitric oxide), CO (carbon monxide)
109
Second messenger example of lipids
DAG
PIP3 (phosphatidylinositol-3,4,5-triphosphate)
PIP2 (PI-4,5-bisphosphate)
sphingosine-1-phosphate
PA (Phosphatidic acid)
110
What is the first second messenger to be transcribed?
cAMP
111
First messengers in signaling pathways are often what?
extracellular hormones
112
What is a plasma membrane IMP in animal cells that is regualte din various ways?
adenylyl cyclases
113
Adenylyl cyclases are generally stimulated by what?
G_s
114
cAMP is extruded from cells via what?
ATP-driven anion pump
115
How is cAMP hydrolyzed to 5'-AMP?
by a cyclic nucleotide phosphodiesterase family
116
What 2 is activated by cAMP?
a. cAMP-dependent protein kinase
b. bacterial cAMP-regulated transcription factor
117
PKA (protein kinase A) is a ____ kinase
serine
118
Structure of PKA
tetramer with 2 (C) catalytic and 2 (R) regulatory subunits
119
___ subunit binds to __- subunit, keeping ____ inhibited
R;C;C
120
What does each R bind to?
2 molecules of cAMP and 4 molecules per PKA holoenzyme
121
When the sites are filled, what happens?
R dimer dissociates rapidly, leaving the 2 free C subunits with high activity
122
PKA can be targeted to specific locations by binding to what?
organelle-associated scaffolds (A-kinase anchoring proteins)
123
AKAPs
A-kinase anchoring proteins
124
Function of AKAPs
facilitate phosphorylation of various membrane proteins including GPCRs, transporters, and ion channels
125
AKAPs have binding sites for what?
phosphoprotein phosphatases and other protein kinases
126
The binding sites of AKAPs allow for what?
coordination of multiple signaling pathways - output integration
127
What is an even more widespread second messenger than cAMP?
Ca2+
128
Why are Ca2+ binding proteins sensitive to an influx of Ca2+ in response to a signal?
free cytosolic [Ca2+] is kept low
129
Ca2+ selective channels in ____ are opened, allowing Ca2+ to ____.
ER or PM; quickly enter the cytosol
130
What are 2 example Ca2+ selective channels in the ER or PM opened to allow Ca2+ to enter the cytosol?
a. plasma membrane electrically gated channels
b. ER Ca2+ channel that is opened by IP3
c. ER electrically gated channels
131
A Ca2+ sensor
Calmodulin
132
What does calmodulin to become fully active and be able to bind its targets?
4 molecules of Ca2+ to bind
133
6 liquid second messengers
a. PI
b. PIP3
c. DAG
d. IP3
e. PA
f. PIP2
134
PLC alters concentration of what 3 second messengers?
a. phospholipids -> DAG + phosphate ester
b. PIP2 -> DAG + IP3
135
What second messenger is hydrophobic and limited to membrane sites?
DAG
136
Function of DAG (3)
a. activates some forms of PKC
b. modulates activity of several cation channels
c. activates at least one another protein kinase
d. hydrolyzed to release arachidonic acid
137
Function of arachidonic acid
regulates some ion channels
138
Arachidonic acid can be converted into what?
prostaglandins and thromboxanes
139
PKC activation requires which 3 interactions?
a. interaction with DAG
b. interaction with Ca2+
c. interaction with an acidic phospholipid such as PS
140
Different groups of PKCs share what?
some patterns of regulation
141
N-terminus of PKCs have what domain?
pseudosubstrate domain
142
Pseudosubstrate binds to ___ to ____ kinase
active site; inhibit
143
To activate PKCs, what 2 needs to happen?
a. cause the pseudosubstrate to flip out of the active site
b. proteolyze a flexible hinge region to lose the autoinhibitory domain
144
What mimic DAG and activate PKC?
phorbol esters (tumor promoters)
145
PLC generates ____ and ____.
DAG; IP3
146
A soluble second messenger
IP3
147
IP3 causes what?
Ca2+ channel in the ER to open
148
At least 6 families of selective PLC enzymes target ___
PIP2
149
How are 6 families of selective PLC enzymes stimulated?
a. all by Ca2+
b. some by binding to a variety of G-protines
c. some by phosphorylation
150
Function of PLA_2
hydrolyzes glycerol phospholipids
151
PLA_2 hydrolyzes glycerol phospholipids to produce what 2?
a. the cognate lysophospholipid
b. free fatty acid (often arachidonic acid)
152
PLD hydrolyzes glycerol phospholipids to produce what 2?
a. 3-sn-phosphatidic acid (PA)
b. a polar head group
153
PLD works on what?
PC
154
Function of PA
secretion and intracellular membrane fusion
155
Function of PI 3-kinase
phosphorylates PIP2 -> PIP3
156
The increase in PIP3 by PI 3-kinase is vital for altering what?
altering cell shape and motility
157
PIP3 recuits protein with what domain?
PIP3-binding domains
158
PIP3 recruits proteins that have what 2 domains?
a. PH domains (pleckstrin homology)
b. FYVE domain
159
Proteins recruited by PIP3 can then regulate what 2?
a. cytoskeletal remodeling
b. contractile protein function
160
Proteins recruited by PIP3 regulate cytoskeletal remodeling and contractile protein function by helping what?
by helping anchor/orient structural or motor proteins
161
PIP3 signaling is important for what?
directing mobility of motile mammalian cells
162
Insulin binds to insulin receptor, where the receptor is what?
Tyr autophosphorylated
163
Insulin binds to insulin receptor, causing activation of effectors via what?
IRS (insulin receptor substrate proteins)
164
IRS
insulin receptor substrate proteins
165
What is activated by binding to IRS1?
PI 3-kinase
166
PI 3-kinase generates what?
PIP3
167
PIP3 binds to protein kinase _______ via their ___ domains
AKt & PDK-1; PH domains
168
PDK-1
phosphoinositide-dependent kinase
169
Akt at the membrane is activated by what?
PDK-1
170
Akt phosphorylates what?
other protein kinases, GAPs, transcription factors
171
Ligand-gated ion channels are ______, membrane spanning proteins
multisubunit
172
Ligand-gated ion channels create and regulate what?
water-filled pore
173
What happens to ligand-gated ion channels upon extracellular agonist stimulation?
subunits rearrange conformation and orientation to open the pore
174
Diffusion of an ion type occurs in ligand-gated ion channels is driven by what?
electrical/chemical gradients
175
What mechanism is found in biology?
fastest signal transduction
176
Following agonist ligand binding, channels open within ______.
microseconds
177
Compared to the channels, receptor-stimulated G proteins take _______ to exchange GDP for GTP
~100 milliseconds
178
What is even slower than channels and receptor-stimulated G proteins?
Receptor protein kinases
179
In contrast to other receptor signaling mechanisms, ion channeling signaling does not have _______ nor _______.
no immediate protein target; specific second messenger involved
180
______ or ______ modulates electrically-driven transport processes for metabolites or ions
channel-mediated ion flow; th cell's membrane potential
181
Animal cells maintain what 4?
a. inside-negative membrane potentials
b. Na+ pumped out (more concentrated outside)
c. K+ pumped in (more concentrated inside)
d. Na+/K+ ATPase: 3Na+ out for 2K+ in
182
Opening a channel selective for Na+ will ______ cells
depolarize cells
183
Opening a channel for K+ will ____ cells
hyperpolarize
184
Opening Cl- channels with ____ cells
hyperpolarize
185
What are 4 examples of ion channels?
a. nicotinic acetylcholine receptor
b. glutamate (Glu) receptors
c. GABA receptors (gamma-aminobutyric acid)
d. Glycine (Gly) receptors
186
What are the 2 cation ion channels?
a. Nicotinic acetylcholine receptors
b. glutamate receptors
187
The nicotinic acetylcholine receptor cation channel function
Na+ influx, depolarizing the membrane
188
The nicotinic acetylcholine receptor is an excitatory receptor at the _____.
Neuromuscular synapse
189
The nicotinic acetylcholine receptor at the neuromuscular synapse in muscles function
membrane depolarizing activates a voltage-sensitive Ca2+ channels, Ca2+ is released into the cytosol, Ca2+ is the 2nd messenger to initiate contraction
190
The nicotinic acetylcholine receptor at the neuromuscular synapse in some secretory cells function
influx of Ca2+ triggers exocytosis
191
Glutamate receptors are ___
neuronal activators
192
Glutamate receptors have ____ family which is permeant to __ and ____.
NMDA; Ca2+; Na+
193
What 2 examples of an anion channels?
a. GABA receptors (gamma-aminobutyric acid)
b. Glycine receptors
194
GABA receptor function
allows inward influx of Cl-, hyperpolarizing the target cells
195
Glycine receptor function
allow inward influx of Cl-, hyperpolarizing the target cell
196
Ligands for ____ pass unaided through the plasma membrane
nuclear receptors
197
Following the ligand binding, the receptors are able to bind to what?
DNA and transcription regulatory proteins
198
What are 13 examples of ligands?
a. estrogen
b. testosterone
c. oxysterols
d. cortisol
e. aldosterone
f. progesterone
g. fatty acids
h. retinoids
i. vitamin A
j. vitamin D
k. carbon monoxide
l. bile acids
m. nitric oxide
199
What are 3 domains do nuclear receptors have?
a. C-terminal ligand-binding domain
b. N-terminal region that interact with transcriptional machinery
c. centrally-located zinc finger domain to bind to DNA
200
With no ligand, receptors is bound to what?
corepressor protein to suppress its activity
201
With ligand, what happens to the corepressor and receptor is bound to what?
corepressors dissociate and receptors are assembled with coactivators
202
Activated nuclear receptors bind to what?
hormone response elements (usually short direct or inverted repeats) in the 5' UTR (untranscribed region) of regulated genes
203
GPCRs
G protein coupled/linked receptors
204
What are GPCRs associated with?
heterotrimeric G proteins
205
What are extremely widespread and found in all eukaryotes?
GPCRs (G protein coupled/linked receptors)
206
GPCRs are used to do what?
respond to examples of every type/class of signaling molecule
207
What are 7-pass transmembrane IMPs?
GPCRs
208
Binding of agonist ligand on the extracellular face causes what?
conformational changes such that the heterotrimeric G protein on the c-face is activated
209
Heterotrimeric G proteins are composed of what?
a nucleotide-binding G_alpha subunit and G_betagamma subunit dimer
210
Why is G_alpha membrane-associated?
because N-terminal acylation and due to interaction with G_betagamma
211
What are G_betagamma?
stable dimers that are prenyl-anchored to the membrane
212
What are 7 examples of effectors for heterotrimeric G proteins?
a. Adenylyl cyclase
b. protein kinases
c. cyclic GMP phosphodiesterase
d. ion channels
e. PLC-beta
f. membrane transport proteins
g. PI 3-kinase
213
Some effectors can bind to either ___ or ___.
Galpha_s; Galpha_i
214
Many effectors are further regulated by what 2?
phosphorylation and binding of allosteric ligands
215
When will Galpha be active?
when GTP is bound
216
Function of Galpha
it has GTPase activity and hydrolyzes its bound GTP to GDP and renders itself thus (Galpha-GDP) inactive
217
GPCRs act as what?
GEFs (guanine nucleotide exchange factors)
218
Why does GPCRs act as GEFs?
because when an agonist ligand is bound to the GPCR, it acclerates both GDP association from Galpha and GTP association
219
Which association is direct for GPCR?
GDP association
220
Which association is indirect for GPCR?
GTP association
221
Why is GTP associated indirectly?
because Galpha has a higher affinity for GTP compared to GDP and because the cytosolic [GTP] is ~20X higher than [GDP]
222
Galpha hydrolysis of bound to GTP to GDP is accelerated by what?
GTPase-activating proteins (GAPs)
223
2 Families of GAPs for heterotrimeric G proteins
a. RGS proteins (regulators of G protein signaling)
b. phospholipase C-betas
224
RGS proteins
regulators of G protein signaling
225
2 Function of RGS proteins (regulators of G protein signaling)
a. regulate G protein signaling rates and amplitudes
b. acts as G protein-regulated effectors
226
2 Examples of RGS proteins (regulators of G protein signaling)
a. Rho family of monomeric GTP-binding protein
b. GPCR kinases
227
What are phospholipase C-betas?
effectors stimulated by both Galphaq and by Gbetagamma
228
What does Gbetagamma inhibit?
the release of GDP (minimizes spontaneous activation) and GAP activity
229
Monomeric G-proteins are homologous to what?
to the GTP-binding domains of G_alpha subunits
230
Monomeric G-proteins are controlled by what?
GTP binding and hydrolysis cycle similar to that of heterotrimeric G proteins
231
What helps regulate monomeric G-proteins?
GEFs and GAPs
232
What slows spontaneous nucleotide exchange and activation?
GDIs (GDP dissociation inhibitors)
233
GDI slows spontaneous nucleotide exchange and activation resulting in what?
dampening of basal activity
234
What are some examples of monomeric G proteins?
a. Ran GTPase
b. Ran-GTP
c. Ran-GDP
d. Ran GEF
e. Ran GAP
235
What were the first small GTP-binding proteins to be discovered?
Ras proteins
236
What are among the most commonly mutated genes in human tumors?
Ras proteins
237
Ras proteins are ______ product
oncogene
238
When does ras proteins cause malignant growth?
if they are over-expressed or if they are persistently activated by mutation
239
Ras GEFs and GAPs are regulated by both ___ and ____
receptor and non-receptor tyrosine kinases
240
Some ______ help activate Ras
cytoplasmic serine/threonine kinases
241
What is the best known and best studied Ras effector?
protein kinase Raf
242
What is the target of Raf?
MAPK
243
Raf targeting MAPK result in what?
protein kinase cascade
244
PI 3-kinase effector target what?
AKt
245
PI 3-kinase targeting Akt result in what function?
lipid kinase
246
Effector RalGDS target what?
exocyst
247
RalGDS targeting exocyst result in what function?
exchange factor
248
What is the most common form of regulatory posttranslational modification to proteins?
phosphorylation
249
__ of animal proteins are at some time point phosphorylated
~1/3
250
Phosphorylation can ___ or ____
stimulate; inhibit
251
Phosphorylation can influence ____ and _____
localization; stability
252
Are kinases and phosphatases regulated?
yes
253
What is an additional protein phosphorylating system in bacteria, plants, and fungi?
two-component signaling
254
Two-component signaling involve different classes of ____ which does what?
protein kinases; phosphorylate aspartate residues
255
Kinases transfer phosphoryl group from ___ to ___
ATP to Ser, Thr, and Tyr residues of protein substrates
256
In animals, ~90-95% of kinase phosphorylation is on ___ with ___ phosphorylated least frequently
Ser residues; Tyr
257
Ser protein kinases are usually ____ protein kinases
Ser-Thr
258
Most tyr kinases recognize and phosphorylate only ___
Tyr
259
What kinases can phosphorylate Ser, Thr, or Tyr in a very restricted substrate conformation?
dual specificity protein kinases
260
Human genome contains _____ encoding protein kinases
~500 genes
261
mRNAs of human genome gene under go ____ to yield even more different kinase enzymes
alternative splicing
262
A portion of a genome that encodes proteins
proteome
263
A portion of a proteome that encodes protein kinases
kinome
264
AGC group is named for which family members?
PKA, PKG, and PKC
265
What kind of kinase is PKA?
cAMP dependent protein kinase
266
What kind of kinase is PKG?
cGMP dependent protein kinase
267
What kind of kinase is PKC?
Ca2+ and phospholipid-dependent protein kinase
268
CaMK
calcium/calmodulin-dependent protein kinases
269
CaMK group comprises what family?
family of serine/threonine kinases
270
TK
Tyrosine kinase
271
TK group comprises what family?
family of enzymes that phosphorylate tyrosine residues on target proteins
272
Most protein kinases are selective for what?
local sequence surrounding the substrate site
273
Of the receptor protein kinases, some are ____ and most are ____
protein serine/threonine kinases; protein tyrosine kinases
274
Examples of protein tyrosine kinases
a. insulin receptor
b. EGF receptor
c. PDGF receptor
275
Where are two-component systems found in?
prokaryotes, plants, and fungi
276
Two-component systems have ___ that receives the stimulus and ____ that initiates cellular responses
receptor (sensor); effector (response regulator)
277
Upon stimulus receipt, the sensor undergoes ____ on _____ , then the sensor transfers the phosphate to ____ on ___, thus activating it.
autophosphorylation on His residue; aspartate residue on regulator
278
Regulator is active until when?
until its phosphate is removed via hydrolysis
279
Most of what inhibitors compete with ATP binding?
pharmacological
280
Inhibitors against protein tyrosine kinases such as ______ have experienced success in the clinic
EGF receptor
281
What phosphatases are regulated by association with other proteins?
protein-serine/threonine phosphatases
282
PP1
phosphoprotein phosphatase 1
283
PP2A
phosphoprotein phosphatase 2A
284
PP1 associates with a variety of ____ that direct it to relevant organelles
regulatory subunits
285
PP2A has separate ___, ____, and _____ subunits
catalytic, scaffolding, and regulatory
286
What are 3 natural toxin inhibitors of PP2A and PP1?
a. okadaic acid
b. calyculin
c. microcystin
287
What is one of several dinoflagellate-produced toxins?
okadaic acid
288
Okadaic acid are eaten by ___, toxins are concentrated, and when humans eat them, it results in ____.
shellfish; Diarrheic shellfish poisoning (DSP)
289
What is a toxin from the marine sponge Discodermia calyx?
Calyculin
290
What is a hepatotoxin prouced by cyanobacteria, especially Microcystis aeruginosa?
microcystin
291
What is microcytis aeruginosa?
a cyclic, nonribosomal peptide
292
_____ aka PP2B
Calcineurin
293
Calcineurin regulated by what?
Ca2+ calmodulin
294
What is calcineurin important in?
in cardiac development and T cell activation
295
What are 2 immunosuppressants that inhibit calcineurin?
a. cyclosporin
b. FK506
296
PTPs
protein tyrosine phosphatases
297
What are cysteine-dependent enzymes?
PTPs (protein tyrosine phosphatases)
298
____ is AKA SHPTP2
SHP2
299
What is a protein tyrosine phosphatase that binds to certain tyrosine kinase receptors?
SHP2
300
SHP2 binds to certain tyrosine kinase receptors via _____.
SH2 domain
301
What are major functions of SHPTP2?
to transduce tyrosine kinase signal and to remove phosphates
302
What recognizes cyclin-dependent kinase family members as substrates?
Cdc25 phosphatases
303
Cdc25 phosphatases plays a roles in what?
increasing Cdk activity at key points in the CDC
304
What works on a restricted number of substates?
Dual specificity phosphatases (DSPs)
305
What are examples of DSPs that dephosphorylate MAPKs?
MAP kinase phosphatases (MKPs)
306
DSPs
dual specificity phosphatases
307
MKPs
MAP kinase phosphatases
308
Ubiquitin is a member of a family of protein known as ____ proteins
Ubl (ubiquitin-like)
309
Functions of Ubl proteins
protein degradation via proteasome and signal transduction
310
What can change protein's behavior to induce downstream signals?
mono- and poly-ubiquitination occur
311
What is monoubiquitination important for?
for regulation of vesicular trafficking and DNA repair
312
What Ubl protein is important for nuclear transport, transcription, and CDC progression?
SUMO
313
How does polyubiquitination occur?
when ubiquitins are attached to other ubiquitins on lysine residues
314
Addition of polyubiquitin with a ___ linkage directs proteins to the proteasome
K48
315
Addition of polyubiquitin with a ___ linkage promotes signal transmission
K63
316
NK-kB inactive in the cytoplasm when bound to ____.
I-kB
317
With a proper signal, I-kB is phosphorylated by ____.
I-kB kinase (IKK)
318
IKB phosphorylated by IKK is recognized by ___
E3 ligase
319
The ubiquination and degradation of I-kB results in what?
NLS on NF-kB to be recognized
320
NLS on NF-kB is recognized by what?
importin
321
When the NLS on NF-kB is recognized by an importin, it allows NF-kB to?
enter the nucleus and function as transcription factor
322
I-KB is stabilized via ____
sumoylation
323
What is sumoylation
covalent attachment of the ubl sumo
324
IKK is regulated by what?
ubiquitination and phosphorylation
325
What are extracellular ligands that are glycosylated and has a covalently bound palmitate?
Wnt proteins
326
What does Wnts bind to?
several receptors including the Frizzled family
327
Frizzled family structure
7-pass transmembrane IMPs
328
Wnt pathways functions in what 5?
a. embryonic development
b. adult morphogenesis
c. body patterning
d. axis formation
e. cell motility
329
Structure/position of receptor tyrosine kinase
transmembrane IMPs
330
Receptor tyrosine kinases are activated by ___ for growth, proliferation, and development
growth factors
331
Receptor tyrosine kinases includes receptors for what?
insulin, EGF, PDGF
332
Mutations that activate receptor tyrosine kinases are often ____.
oncogenic
333
Receptor tyrosine kinases have __ membrane span per ____
one; monomer
334
Ligand binding to receptor tyrosine kinases favor ____, enhances _____ leading to increased _____ of the intracellular domain of the receptor and associated molecules
receptor oligomerization; kinase activity; Tyr phosphorylation
335
Autophosphorylated receptor tyrosine kinases bind to SH2 domain containing proteins like what? (5)
a. PLC-gamma
b. PI 3-kinase
c. Src
d. Ras GAP
e. SHP2 tyrosine phosphatase
336
The SH2 domain containing proteins are _____ what are phosphorylated on tyrosine residues
receptor substrates
337
What is an example of a receptor tyosine kinase?
insulin receptor
338
Insulin binding to insulin receptor causes what?
receptor tyrosine kinase activation
339
Insulin receptors are responsible for attraction and phosphorylation of __ proteins
IRS
340
IRS proteins binds via ____ to activate what?
SH2 domain; PI 3-kinase
341
Activation of PI 3-kinase leads to activation of what?
AKT-2
342
Function of AKT-2
helps bring about enhanced glucose uptake, and increased glycogen synthesis
