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EoM 3 > Cell Signalling > Flashcards

Cell Signalling Flashcards

1
Q

Signaling molecules are released from secretory cells into the blood and carried to distant target tissues

A

Endocrine signaling

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2
Q

Signaling molecules exert their effects locally on neighboring cells: they reach these target cells via the interstitial fluid

A

Paracrine signaling

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3
Q

Signaling molecules bind to receptors in or on the cells that release them

A

Autocrine signaling

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4
Q

Concentration of ligan at which 1/2 of the receptors are occupied

A

Kd

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5
Q

Kd = ?

A

[L][R] / [LR}

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6
Q

The slope of a receptor-ligand binding graph is?

A

-Ka

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7
Q

Adrenergic receptor type in vascular smooth muscle

A

alpha-1

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8
Q

Adrenergic receptor type in pancreatic beta cells

A

alpha-2

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9
Q

Adrenergic receptor type in liver, bronchial smooth muscle, and adipose tissue

A

beta-2

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10
Q

Adrenergic receptor type in the heart

A

beta-1

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11
Q

What do adrenergic receptors bind?

A

catecholamines

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12
Q

ACh receptors in the parasympathetic nervous system have a high specific affinity for…

A

muscarine (muscarinic receptors)

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13
Q

ACh receptors in the skeletal muscle have a high specific affinity for…

A

nicotine (nicotinic receptors)

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14
Q

Structural analog of a naturally occurring signaling molecule that binds the receptor for that signaling molecule and mimics the responses induced by the naturally occurring molecule

A

agonist

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15
Q

structural analogs that bind a receptor for a signaling molecule but do not elicit a response. Since they interfere with the binding of the naturally occurring signaling molecule to the receptor, they block the action of that signaling molecule.

A

antagonist

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16
Q

What type of channel is a nicotinic acetylcholine receptor?

A

Ligand-gated cation channel

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17
Q

Largest family of enzyme-linked receptors that have activity in the cytoplasmic domain of the receptor

A

receptor tyrosine kinase family

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18
Q

Largest family of cell surface receptors in the human genome

A

G protein-coupled receptors (GPCRs)

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19
Q

The extracellular N domain of G protein coupled receptors has how many loops?

A

3

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20
Q

What are the three subunits of G proteins?

A

alpha, beta, gamma

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21
Q

Subunit(s) of G proteins which are tethered to the plasma membrane by covalent bond with membrane lipids

A

alpha and gamma

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22
Q

Which G protein subunits stay coupled during signaling?

A

beta and gamma

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23
Q

G proteins are ____ when GTP occupies the guanine nucleotide binding site

A

active

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24
Q

G proteins are ____ when GDP occupies the guanine nucleotide binding site

A

inactive

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25
Q

In GPCRs, what has GTPase activity

A

alpha subunit

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26
Q

Plasma membrane associated enzyme that catalyzes the conversion of ATP to cycle AMP (cAMP)

A

Adenylyl cyclase

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27
Q

Stimulatory G protein (stimulates adenylyl cyclase activity)

A

Gs

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28
Q

Inhibitory G protein (inhibits adenylyl cyclase activity)

A

Gi

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29
Q

What happens when an extracellular signaling molecule binds to a GPCR

A

It acts like a guanine nucleotide exchange factor, facilitating the release of GDP and binding of GTP to the alpha subunit

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30
Q

What happens when Gαs binds to its target?

A

Adenylyl cyclase is activated, catalyzing the conversion of ATP to cAMP.

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31
Q

What does the beta-gamma complex activate in some instances?

A

ion channels

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32
Q

What does cAMP activate in the GPCR cascade?

A

Protein Kinase A

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33
Q

How is Protein Kinase A activated?

A

cAMP binding to the regulatory subunit causes the regulatory and catalytic subunits to dissociate

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34
Q

What does phosphodiesterase convert cAMP to?

A

5’ AMP

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35
Q

Which residues does PKA phosphorylate?

A

Ser and Thr

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36
Q

What does the catalytic subunit of PKA phosphorylate to activate in the nucleus?

A

CREB

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37
Q

The phosphorylated CREB dimer binds to what in the regulatory region of cAMP-inducible genes

A

cAMP Response Element (CRE)

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38
Q

The coactivator protein that links phosphorylated CREB with the basal transcription machinery

A

CBP/300

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39
Q

Preferential targeting of PKA-mediated phosphorylation to specific subcellular location can be achieved by means of _____

A

A-Kinase Anchoring Proteins (AKAP)

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40
Q

A-Kinase Anchoring Proteins (AKAP) are what kind of proteins?

A

Scaffolding proteins. This allows PKA to be integrated with other signaling events.

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41
Q

cAMP induces most of its actions by activating PKA. What else does it have a direct effect on?

A

ion channels

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42
Q

What enters intestinal epithelial cells and induces a process that modifies Gsα, blocking GTPase activity. Gs stays active.

A

Cholera Toxin

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43
Q

Herbal extract from the plant Coleus forskohlii which has a direct stimulatory effect on adenylyl cyclase

A

forskolin

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44
Q

Caffeine inhibits…

A

phosphodiesterase activity

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45
Q

Beta-adrenergic receptor agonist

A

isoproterenol

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46
Q

Beta-adrenergic receptor antagonist

A

propranolol

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47
Q

In M2 muscarinic receptors in the heart, beta-gamma subunits released by Gi do what?

A

Bind to and open K+. Efflux of K+ hyperpolarizes the plasma membrane.

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48
Q

Toxin that covalently modifies Gαi so that it stays in the GDP form (inactive)

A

pertussis toxin

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49
Q

Five ways to terminate the GPCR/cAMP signaling pathway?

A

1) dissociation and degradation of signaling molecules
2) intrinsic GTPase activity
3) phosphodiesterase
4) phosphatase action on PKA-phosphorylated proteins
5) GPCR down-regulation

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50
Q

GTPase activity of the G alpha subunit can be enhanced by what?

A

Regulatory of G protein signaling proteins (RGS)

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51
Q

A state of reduced responsiveness of a tissue to an agonist that develops in response to the continuous or repeated stimulation of the tissue by that agonist

A

Densensitization

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52
Q

Two things that can desensitize Gs protein-coupled receptors

A

1) receptor phosphorylation by PKA

2) beta-arrestin binding to the receptor

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53
Q

In beta-adrenergic receptors, how does feedback inhibition by PKA work?

A

PKA phosphorylates Ser/Thr residues nearby the cytosolic domain of Gs which usually interact with and activate Gs, diminishing the response of the target tissue to further stimulation by epinephrine.

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54
Q

Kinases that phosphorylate specific serine and threonine residues on the cytosolic domain of G protein-coupled receptors only when the receptor is in an active conformation induced by the occupation of the ligand-binding site by a compatible hormone or agonist.

A

G protein-coupled receptor kinases (GRKs)

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55
Q

The serine and threonine residues phosphorylated by beta-ARK serve as binding sites for ____

A

beta-arrestin

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56
Q

Recruited to the plasma membrane where it phosphorylates specific serine and threonine residues on the beta-adrenergic receptor.

A

Beta-Adrenergic Receptor Kinases (beta-ARK)

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57
Q

Binding of beta-arrestin to the phosphorylated receptor blocks what?

A

It blocks the coupling of G proteins with the receptor

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58
Q

Do PKA and beta-ARK target the same or different serine/threonine residues?

A

different

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59
Q

What recruits beta-ARK to the membrane?

A

Gsβγ

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60
Q

Which two proteins does beta-arrestin work with to promote endocytosis of receptors?

A

Clathrin and AP2 (components of clathrin-coated pits)

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61
Q

Why does receptor endocytosis result in a net decrease in the receptor content of the plasma membrane?

A

Some are degraded

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62
Q

What happens to endocytosed receptors which will be recycled?

A

Dephosphorylated and translocated back to the plasma membrane

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63
Q

How does beta-arrestin link the GPCR to other signal transduction pathways?

A

GPCR-arrestin complex forms a scaffold that binds to and activates cytosolic kinases that trigger signal transduction(s)

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64
Q

What does Gq’s alpha subunit bind to and activate?

A

phopholipase c (beta form)

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65
Q

What does phospholipase C-beta cleave?

A

PIP2

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66
Q

What does PIP2 get cleaved into?

A

IP3 and DAG

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67
Q

Lipophilic molecule that remains in the plasma membrane where it binds to and activates certain isoforms of protein kinase c

A

DAG

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68
Q

IP3-gated Ca2+ release channels are located where?

A

endoplasmic reticulum

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69
Q

What triggers the recruitment of protein kinase C to the plasma membrane

A

calcium

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70
Q

Protein Kinase C phosphorylates what kinds of residues

A

Ser/Thr

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71
Q

Which isoforms of PKC have a regulatory subunit with Ca2+ and DAG binding sites and their activation requires Ca2+, DAG, and a membrane phospholipid

A

Conventional Isoforms

72
Q

A rise in cytosolic Ca2+ induces conventional isoforms of PKC to do what?

A

Translocate to the plasma membrane where they become activated

73
Q

What type of ion can IP3 open channels for?

A

Ca2+ (IP3-gated Ca 2+ release channels)

74
Q

What replenishes depleted Ca2+ stores in a cell?

A

Plasma membrane store-operated channels

75
Q

Ca2+, when high in the ER lumen, bind to the EF hand region on what transmembrane protein?

A

Stromal Interacting Molecules (STIM)

76
Q

How do STIM proteins bind to and open Orai 1 store-operated channels to bring extracellular Ca2+ into the cell?

A

Ca2+ dissociates from STIM when low, forming an oligomeric complex which translocates to areas of the ER close to the plasma membrane, opening store-operated channels

77
Q

Transports Ca2+ out of the cell and into the ER; Ca is coupled to the expenditure of metabolic energy

A

CA2+ ATPases

78
Q

What does PMCA stand for?

A

Plasma membrane Ca2+ ATPases

79
Q

What is SERCA?

A

ATPases in sarcoplasmic and endoplasmic reticulum

80
Q

An antiporter that utilizes sodium influx into the cell along its concentration gradient to move Ca2+ out of the cell.

A

Na+-Ca2+ Exchanger (NCX)

81
Q

The activity of Voltage-Gated Ca2+ Channels can be modulated by… (3)

A

1) phosphorylation
2) G proteins
3) drugs and toxins

82
Q

When do voltage-gated Ca2+ channels typically close

A

normal resting membrane potential

83
Q

What type of channel is the IP3-gated Ca2+ release channel in the ER?

A

ligand-gated

84
Q

Receptor type in which Ca2+ entering cardiac muscle cells through voltage-gated channels can further increase local Ca2+ concentration by binding to and opening to these calcium release channels in the sarcoplasmic reticulum

A

Ryanodine receptor

85
Q

How many Ca2+ binding sites does calmodulin have?

A

four

86
Q

What is the intrinsic enzymatic activity of calmodulin?

A

it has none

87
Q

What do the four calcium binding sites on calmodulin contribute to?

A

positive cooperativity

88
Q

Four examples of regulation by calmodulin

A

1) cyclic nucleotide phosphodiesterase
2) plasma membrane Ca2+-ATPase
3) Ca2+/CaM-dependent protein kinase II
4) myosin light-chain kinase

89
Q

What protein kinase is found in most tissues but occurs in especially high concentrations in neurons?

A

Ca2+/CaM-dependent protein kinase II

90
Q

The catalytic domain of Ca2+/CaM-dependent protein kinase II is blocked by what in the basal (inactive) state?

A

autoinhibitory domain

91
Q

What allows Ca2+/CaM-dependent protein kinase II to remain active after the calcium concentration of the cytosol falls to resting levels?

A

Autophosphorylation

92
Q

A mechanism of antagonistic interaction between the two pathways, cyclic nucleotide phosphodiesterase activity is enhanced by what?

A

Ca2+/CaM

93
Q

How can protein kinase A interact with the Ca2+ second messenger pathway?

A

PKA can phosphorylate some voltage-gated Ca2+ channels

94
Q

PKA and Ca2+/CaM-dependent kinase both phosphorylate what?

A

CREB

95
Q

Transmembrane cell surface receptors that possess tyrosine kinase activity in their cytoplasmic domain

A

Receptor tyrosine kinases

96
Q

Most of these receptor types are single-chain polypeptides that exist as monomers in the absence of ligand binding

A

Receptor tyrosine kinases

97
Q

What receptor type consists of:

1) an extracellular domain that contains a binding site for signaling molecules
2) a single hydrophobic transmembrane alpha-helix
3) a cytoplasmic domain catalytic domain and several autophosphorylation sites

A

receptor tyrosine kinases

98
Q

What happens after ligand binding with receptor tyrosine kinases?

A

Ligand binding induces two receptor monomers to dimerize

99
Q

Dimerization leads to what in receptor tyrosine kinases?

A

autophosphorylation. This area is called the activation loop

100
Q

Fully active domains of receptor tyrosine kinases phosphorylate… (2)

A

1) cytosolic segments of the receptor dimer. These phosphotyrosines act as docking sites for intracellular signaling molecules
2) intracellular signaling molecules, transmitting the signal further downstream

101
Q

Insulin and IGF-1 receptors are submembers of what category?

A

Receptor tyrosine kinases

102
Q

Structure of insulin receptor (its subunits)

A

two external alpha subunits and 2 transmembrane beta units, bound together by disulfide bridges

103
Q

Where is the ligand binding site on the insulin receptor? where is the tyrosine kinase domain?

A

Ligand binding site - alpha

Tyrosine kinase domain - beta

104
Q

What is one of the major targets of insulin receptor tyrosine kinase activity?

A

Insulin Receptor Substrates (IRS)

105
Q

What do the phosphotyrosine residues of IRS do?

A

Serve as a docking site for other intracellular signaling proteins

106
Q

Various intracellular signaling proteins (multiple) can recognize and dock with phosphotyrosines on the IRS by means of what domain?

A

Their SH2 domains

107
Q

What is a critical negative regulator of insulin and IFG signaling (important to prevent tumor formation and metabolic abnormalities)

A

Phosphotyrosine phosphatases

108
Q

Purpose of intracellular signaling proteins binding to phosphotyrosines on the RTK? (3)

A

1) localizes them to the plasma membrane
2) enables them to interact with other proteins that are associated with the receptor
3) activates the signal transduction pathways to which the intracellular signaling proteins are coupled

109
Q

Besides SH2 domains, intracellular signaling proteins can associate with receptor phosphotyrosines by means of which domain?

A

Phosphotyrosine binding domains (PTB)

110
Q

Highly conserved region of about 100 amino acids on intracellular signaling proteins

A

SH2

111
Q

PLC-γ (phospolipase C isoform gamma) can be activated by…

A

receptor tyrosine kinases

112
Q

Negative regulator of Ras

A

GAPs (GTPase-activating protein), because they promote GTP hydrolysis

113
Q

Positive regulator of Ras

A

GEFs (Guanine nucleotide exchange factor) because they promote the release of GDP, which is then replaced by GTP

114
Q

Ras inactive/off state

A

GDP bound

115
Q

Ras active/on state

A

GTP bound

116
Q

What activates the Ras/MAP kinase pathway

A

receptor tyrosine kinases

117
Q

Cell signaling pathway playing an important role in regulating cell proliferation and differentiation

A

MAP kinase pathway

118
Q

Raf, MEK, and MAPK are kinases activated in what pathway?

A

MAP (mitogen-activated protein) kinase pathway

119
Q

What makes up the adaptor/guanine exchange factor complex connecting the receptor tyrosine kinase and activating Ras?

A

GRB2/Sos

120
Q

Virtually all receptor tyrosine kinases are capable of activating which pathway?

A

Ras/MAP pathway

121
Q

MAPK inducts gene transcription by phosphorylating which two transcription factors?

A

SRF (indirectly through p90RSK) and TCF

122
Q

Family protein/peptide signaling molecules that play a major role in regulating the proliferation and differentiation of blood cells and cells of the immune system.

A

Cytokines

123
Q

Cytokine receptors are bound to what in their cytoplasmic domain?

A

Janus Kinase (JAK)

124
Q

JAKs phosphorylate which types of residues

A

Tyrosine

125
Q

Structure of cytokine receptors

A

Typically function as homodimers. The receptor dmer may be preformed before ligand binding or form in response to ligand binding

126
Q

True or false; JAK protein kinases have activation loops

A

true

127
Q

STAT proteins (Signal Transduction and Activation of Transcription) are major targets of _____

A

JAKs

128
Q

What are STAT proteins?

A

Transcription factors located in the cytoplasm

129
Q

These transcription factors have an SH2 domain and require tyrosine phosphorylation for activation

A

STAT proteins

130
Q

How do STAT proteins activate gene transcription

A

They’re first phosphorylated, form dimers, and translocate to the nucleus

131
Q

Inhibits receptor tyrosine kinase activity by phosphorylating specific serine or threonine residues in the cytosolic domain of the receptor

A

Protein Kinase C

132
Q

Prolonged stimulation of certain tyrosine kinase and cytokine receptors by their respective ligands can reduce the number of cell surface by….

A

increasing the rate of receptor-mediated endocytosis

133
Q

Which type of signaling protein can, when bound to the activated receptor, induce ubiquitination

A

SH2

134
Q

SHP1, a phosphotyrosine kinase, acts on which receptor?

A

Erythropoietin receptor

135
Q

One (of the two) SH2 domains binds to and inactivates the phosphatase domain of SHP1. What state is the cell in (stimulated or unstimulated)?

A

Unstimulated

136
Q

When active, the blocking SH2 domain of SHP 1 docks with the phosphotyrosine residue on the erythropoeitin receptor near the catalytic domain of ____. The exposed phopshatase domain of SHP1 removes a phopshate group in the activation loop, reducing the catalytic activity of ____ (both blanks are the same)

A

JAK

137
Q

Phosphatidylinositol 3-phosphate (PI 3-phosphate) does what?

A

activates many cytoplasmic protein kinases

138
Q

PI 3-kinase is able to be recruited to the plasma membrane by which two activated receptors

A

Receptor tyrosine kinases and cytokine receptors

139
Q

What catalyzes the addition of 3-phosphate to phosphoinositide substrates in the plasma membrane to form PI 3-phosphates

A

PI 3-kinase

140
Q

PI 3-phosphates function as _____ sites for certain signal transduction proteins

A

docking sites

141
Q

Plextrin homology (PH) domains bind what with high affinity?

A

3-phosphates

142
Q

Akt is also called

A

Protein Kinase B

143
Q

What kind of kinase is PKB/Akt

A

Serine / Threonine

144
Q

An important kinase that binds to PI 3-phosphates in the plasma membrane is….

A

Akt aka protein kinase B

145
Q

The PH domain of PKB is bound to the catalytic domain in what state

A

unstimulated

146
Q

During stimulation of the cell by a signaling molecule, partial activation is achieve by what binding what

A

PH domain of PKB binds to 3-phosphate groups

147
Q

Full activation of PKB requires which two additional kinases

A

PDK1 and PDK2

148
Q

Fully active PKB plays an important role in what two things

A

1) promoting cell division and survival

2) regulation of metabolism

149
Q

Members of the FOXO family of transcription factors are major targets of ___

A

Akt (PKB)

150
Q

Cytosolic chaperons called 14-3-3 proteins bind Akt (PKB) phosphorylated ____ transcription factors and keep them in the cytosol to stop them from inducing transcription

A

FOXO transcription factors

151
Q

Transcription factor involved in transcription of numerous genes encoding proteins that are involved in inflammatory and immune responses

A

NF-kB

152
Q

What is an example of a gene transcription signaling pathway being regulated by the ubiquitin-mediated degradation of an inhibitor protein

A

NF-kB signaling pathway (inhibitory protein = IκBα)

153
Q

Blocks the translocation of NF-kB to the nucleus

A

IκBα

154
Q

When the cell is subjected to viral infection, ionizing radiation or is exposed to a mediator of inflammation this kinase is activated (NF-kB signaling pathway)

A

I-κB kinase (phosphorylates two serine residues on IκBα)

155
Q

What binds to phosphorylated IκBα to trigger its degradation by proteosomes

A

E3 ubiquitin ligase

156
Q

Protein products of the NF-kB pathway (4)

A

1) phospholipase A2
2) cyclooxygenase
3) NO synthase
4) cytokines (such as TNFα and interleulin-1)

157
Q

One of the genes that NFkB regulates is the gene for IκB. This makes it what type of feedback loop?

A

Negative. IκB returns activated NF-kB to the cytosol

158
Q

Nitric Oxide (NO) is made by the deamination of ______ in a reaction catalyzed by the enzyme NO Synthase

A

arginine

159
Q

What does NO released from endothelial cells do as an example of paracrine signaling?

A

Relaxation of smooth muscle cells in blood vessels

160
Q

The NO released from endothelial cells in response to acetylcholine stimulation diffuses into the underlying vascular smooth muscles cells and activates a soluble form of what enzyme?

A

Guanylyl cyclase

161
Q

The rise in ____ levels promotes vasorelaxation (related to NO signaling)

A

cGMP

162
Q

Vasorelaxation is promoted by which kinase

A

cGMP-Dependent Protein Kinase

163
Q

What do receptors for thyroid hormones, steroid hormones, vitamin D3 and retinoids function as when bound by their ligand

A

transcription factors

164
Q

DNA-binding fingers are featured in pairs in what receptor

A

intracellular receptors

165
Q

What is the hinge region in intracellular receptors

A

a flexible region between the DNA-binding domain and Ligand binding domain

166
Q

In the absence of hormone binding, unoccupied steroid hormones are part of what?

A

multi-protein chaperone complex that includes heat shock proteins

167
Q

Where do steroid hormone receptors bind to the DNA

A

Steroid-response elements (SRE)

168
Q

In hormone-dependent activation of gene transcription, hormone-bound receptor dimers recruit a complex of…

A

coactivator proteins (some of which possess histone acetyltransferase activity!)

169
Q

Androgen receptor antagonist

A

flutamide

170
Q

Progesterone receptor antagonist

A

RU486

171
Q

True or False; Thyroid Hormone Receptors tend to bind tightly to DNA even in the absence of hormone binding

A

true

172
Q

Binding site for Thyroid Hormone Receptors on DNA

A

Thyroid Response elements

173
Q

True or False; Steroid hormone receptors tend to bind tightly to DNA even in the absence of hormone binding

A

false

174
Q

Which hormone receptor family does not form complexes with heat shock proteins when unbound by hormone

A

Thyroid Hormone Receptor Family

175
Q

Thyroid Hormone Receptors heterodimer with which receptor

A

RXR receptor

EoM 3 (10 decks)

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