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MCB 3010 > Cell Signaling > Flashcards

Cell Signaling Flashcards

1
Q

What are PTMs

A

Modifications that occur to a protein that alter its function in some way.

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2
Q

RTKs

A

Directly phosphorylate specific tyrosines on themselves and on a set of intracellular signalling proteins

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3
Q

Ligands are either ______ or ______

A

Soluble of membrane-bound

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4
Q

The three most commonly phosphorylated amino acids in eukaryotes

A

Serine, threonine and tyrosine

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5
Q

What group does phosphorylation occur on

A

Hydroxyl groups (OH)

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6
Q

________ phosphorylation is involved in signal transduction

A

Tyrosine

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7
Q

What side (intra or extracellular) contains ligand binding domain

A

Extracellular

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8
Q

What side (intra or extracelllular) is the effector side

A

Intracellular - effects a protein inside leads to signal cascade, cause alterations within cell

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9
Q

Where is kinase domain and what receptors contain it

A

Intracellular side, receptors that can phosphorylate themselves

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10
Q

Cysteine rich domains are able to

A

Be modified easily, (can respond to oxidative stress and be oxidized) can change ability to respond to ligands

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11
Q

What does ligand binding cause for RTKs

A

Receptor dimerization and cross-phosphorylation called trans-autophosphorylation

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12
Q

Each RTK subunit has a _______ ________ domain

A
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13
Q

How are tyrosine kinase domains activated

A

Domains need to come close enough together to phosphorylate eachother

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14
Q

2 ways the domains coming together (to phosphorylate eachother) is regulated

A

1.Ligand binding brings RTKs close together so kinase domains phosphorylate eachother)
2.Ligand binding triggers a conformational change activating kinase domain of receptor

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15
Q

Transfected means

A

Delivered an artificial construct to cells, cells now expressing receptor with mutation

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16
Q

Cells are transfected with DNA encoding a mutant form of the receptor that can

A

Dimerize but not phosphorylate

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17
Q

What happens with 2 subunits (1 with normal and 1 with mutant TKD) when ligand binds

A

Come together, no cross-phosphorylation since only one has a TKD

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18
Q

Dominant negative mutation

A

Only takes 1 mutant subunit to have mutated effect

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19
Q

Once bound, a signaling protein may become activated by:

A

1) itself becoming phosphorylated on tyrosines (eg IGF and IRS1),
2) binding alone may induce a conformational change
3) simply bringing it near the next protein in the signaling pathway

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20
Q

2 ways Trans-autophosphorylation contributes to RTK activation

A

Increases the kinase activity of the enzyme and creates high-affinity docking sites for intracellular signaling proteins

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21
Q

What happens with a fully active RTK

A

The ligand has bound, brought the 2 subunits close together to allow for trans-auto phosphorylation, that will lead to phosphorylation of tyrosine residues which with then act as docking stations for adaptor molecules

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22
Q

The phospho-tyrosine residue will always bind to some domain in specific proteins, this domain is called an

A

SH2 domain

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23
Q

Intracellular signalling (adaptor) proteins usually share highly conserved

A

phosphotyrosine binding domains SH2 (SRC Homology) domains or PTB (phosphotyrosine binding) domains.

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24
Q

Through these domains, these signaling proteins (SH2 and PTB) can bind to activated RTKs, but also to other phosphorylated intracellular signaling proteins.

A

Activated RTKs, and other phosphorylated intracellular signaling proteins.

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25
Q

SH3 domains bind

A

Proline rich motifs

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26
Q

Split tyrosine kinase domains cause

A

Phosphorylation at different sites

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27
Q

PDGF receptor

A

Start with a signal stimulus – ligand binding and then this signal is amplified, it recruits 3 different protein complexes, all of which are capable of recruiting and interacting with more proteins. These signals get further amplified and you will get the effect of cell proliferation or migration etc

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28
Q

c-Cbl protein decreases the signaling process by

A

Covalently adding a single ubiquitin (monoubiquitylation) to one or more sites on the RTK.

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29
Q

Monoubiquitylation promotes

A

endocytosis and degradation of RTKs by targeting to clathrin-coated vesicles and, ultimately, to lysosomes.

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30
Q

Poly-UUB targets

A

proteins for degredation directly

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31
Q

c-Cbl is an ________ of the RTK signalling pathway

A

Inhibitor

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32
Q

c-Cbl decreases the signaling process by

A

covalently adding a single ubiquitin (monoubiquitylation) to one or more sites on the RTK.

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33
Q

When the cell wants to downregulate response

A

the receptor can be internalized, once the pH changes in the endosome the ligand will dissociate from the receptor and the receptor can be recycled back to the PM

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34
Q

Adaptor proteins are composed almost entirely of

A

SH2 and SH3 domains

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35
Q

Adaptor proteins

A

couple activated RTKs to important signaling proteins that do not have their own SH2 domains, such as Ras.

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36
Q

Activated Ras is

A

Ras-GTP

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37
Q

MAPK (ERK) activated by EGF

A

Plateaus in 5 mins

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38
Q

MAPK (ERK) activated by NGF

A

Lasts for hours

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39
Q

EGF promotes _________ while NGF promotes __________

A

Proliferation, differentiation

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40
Q

How is cross-talk prevented

A

Adaptor proteins

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41
Q

The Rho family

A

regulate the cytoskeleton to control cell shape, polarity, motility and adhesion. (Rho, Rac, CDC42)

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42
Q

Unlike Ras, inactive Rho (with GDP bound) is often not membrane-bound, but bound to

A

guanine nucleotide dissociation inhibitors (GDIs) in the cytosol.

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43
Q

Is inactive Rho membrane bound

A

no

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44
Q

PI-3-kinase

A

PM-bound enzyme, phosphorylates inositol phospholipids instead of proteins

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45
Q

Phosphoinositol (PI) undergoes _________ phosphorylation at ______ ______ on its head group

A

Reversible, multiple sites

46
Q

PI-3-K always leads to phosphorylation of carbon ______, results in formation of ____________

A

3, PI3 phosphates

47
Q

PTEN

A

DEphosphorylates and inactivates PIP3 at C3

48
Q

Akt

A

serine/threonine protein kinase, PH-domain containing

49
Q

The PI-3-kinase-Akt pathway signals cells to grow through a more complex mechanism that depends on a large serine/threonine kinase called _______

A

mTOR

50
Q

mTOR

A

Master regulator of growth, turns on protein translation causes growth

51
Q

PDK1 in the PI-3-kinase-Akt signal pathway

A

phosphorylates and partially activates Akt

52
Q

mTOR in the PI-3-kinase-Akt signal pathway

A

further phosphorylates Akt, causes dissociation from PIP3 dock site

53
Q

Akt promotes ____

A

growth

54
Q

Phosphorylation of Bad

A

releases apoptosis inhibitor

55
Q

Src family

A

cytoplasmic tyrosine kinase

56
Q

Src kinases contain ______ and are located on the ________ side of the PM

A

SH2 & SH3 domains, cytoplasmic side

57
Q

The largest class of receptors that rely on cytoplasmic tyrosine kinases is the class of

A

cytokine receptors

58
Q

Cytokine receptors are stably associated with cytoplasmic tyrosine kinases called ______

A

JAKs

59
Q

JAKs phosphorylate and activate ________

A

STATS

60
Q

STATS go where when activated

A

migrate to the nucleus

61
Q

There are at least six STATs in mammals, each has a _______ domain

A

SH2

62
Q

2 functions an SH2 domain in STATs performs

A

1) mediates the binding of STAT to activated receptor
2) upon STAT release from receptor, mediates the binding to another phosphorylated STAT.

63
Q

TGFβ-receptor serine-threonine kinases signal more directly to the nucleus than the JAK-STAT pathway by directly activating latent gene regulatory proteins called

A

Smads

64
Q

The human transforming growth factor-β superfamily consists of 30-40

A

secreted, dimeric proteins (hormones or local mediators

65
Q

TGFβ-receptor serine-threonine kinases signal more or less directly to the nucleus than the JAK-STAT pathway?

A

More

66
Q

How does TGFβ-receptor serine-threonine kinases signal more directly to the nucleus?

A

directly activating latent gene regulatory proteins called Smads

67
Q

Latent gene regulatory proteins

A

The protein is there and ready to be activated to go directly the nucleus and exert its effects

68
Q

TGFβ-receptor serine-threonine kinases signal

A

-2 monomers brought into close prox. by ligand binding
-TGFβ binding causes type-II receptor to phosphorylate type I receptor
-Type I phosphorylates Smad 2 or 3
-Smad 2 or 3, dissociates from receptor and dimerizes with Smad 4
-Smad 4 goes to nucleus, recruits gene regulatory elements to activate gene trascription

69
Q

Inhibitory Smads (iSMADS) negatively regulate the Smad pathway through 4 various mechanisms:

A
  1. Compete with Smads for bind sites on rec.
  2. Recruit ubiquitin ligases called Smurfs, which ubiquitylate the rec.
  3. Recruit protein phosphatase- removes phosphate groups
  4. Bind to co-Smad (Smad4) prevents Smad 2/3 from binding or promoting its ubiquitylation
70
Q

STATs and Smads are activated by

A

phosphorylation (not proteolysis)

71
Q

Latent gene regulatory proteins activated by phosphorylation

A

STATs and Smads

72
Q

Latent gene regulatory proteins activated by proteolysis

A

receptor protein Notch, the secreted Wnt proteins, the Hedgehog proteins, and the NFκB latent gene regulatory protein

73
Q

the production of nerve cells in Drosophila arise from

A

single cells within an epithelial sheet of precursor cells

73
Q

Notch is best known for its role in

A

the production of nerve cells in Drosophila

74
Q

When a precursor cell commits to becoming a nerve cell, it signals to its immediate neighbors not to do the same by

A

displaying on its surface a transmembrane signal protein called Delta

75
Q

What does the delta ligand do to prevent neighbouring cells from becoming a nerve cell

A

Delta ligand binds to Notch receptors on neighboring cells to prevent them from becoming neural.

76
Q

Nerve cells differentiation is an example of ________ signalling called ________ ________

A

Contant-dependant, lateral inhibition

76
Q

Notch is a ___________ protein that requires _________ processing to function.

A

transmembrane, proteolytic

77
Q

What protein pathway provides the simplest most direct signaling to the nucleus of any known pathway.

A

Notch

78
Q

What happens to Notch when activated by the binding of Delta

A

a protease cleaves the cytoplasmic tail of Notch, and the resulting fragment translocates into the nucleus to activate transcription

79
Q

Wnt proteins bind to ______ receptors and inhibit the degredation of ______

A

frizzled, β-catenin

80
Q

What are Wnt proteins

A

secreted signal molecules with a fatty acid chain covalently attached to their N-terminus to increase their binding to cell surfaces

81
Q

3 intracellular signaling pathways Wnt activates

A

1) The Wnt/β-catenin pathway,
2) The planar polarity pathway,
3) The Wnt/Ca2+ pathway

82
Q

All 3 intracellular signaling pathways Wnt activates begins with

A

-binding of Wnts to Frizzled
-When activated by Wnt proteins, Frizzled recruits the scaffold protein Dishevelled (relays signal down all 3 paths),

83
Q

What is Frizzled

A

Family of cell-surface receptors

84
Q

What is dishevelled

A

Scaffold protein

85
Q

The Wnt/β-catenin pathway acts by regulating the

A

proteolysis of β-catenin, (functions both in cell-cell adhesion and gene regulation)

86
Q

Wnt acts by binding both (2)

A

a frizzled protein and a LDL-receptor-related protein (LRP)

87
Q

Cytoplasmic β-catenin is degraded by a large degradation complex that contains a

A

a serine/threonine kinase (CK1)

88
Q

What does CK2 do in Wnt pathway

A

phosphorylates β-catenin priming it for further phosphorylation by another serine/threonine kinase (GSK3).

89
Q

Final phosphorylation marks β-catenin for

A

ubiquitylation and rapid degradation in proteasomes.

90
Q

What happens in absense of Wnt signal in terms of degredation and signaling

A

β-catenin degraded, no signalling

91
Q

What protein results without Wnt signal and what does it do

A

Groucho, inhibiting the transcription of genes that would be activated in the presence of Wnt.

92
Q

What does mutation of APC complex cause

A

Wnt genes to always be transcribed

93
Q

WITH Wnt signal, what happens in nucleus

A

β-catenin displaces Groucho, allowing for transcirption of Wnt genes

94
Q

What does dishevelled do in WITH Wnt signal

A

dissociates the APC complex by pulling Axin away, CK1 and GSK3 (now free kinases) phosphorylate LRP - how pathway can be turned off

95
Q

Similarities between Hedgehog and Wnt proteins

A

-are secreted signal molecules that act as local mediators in development
-activate latent gene regulatory proteins by inhibiting their proteolysis
-trigger a switch from transcriptional repression to activation

96
Q

What do hedgehog proteins bind and what does that do

A

bind to Patched, relieving its inhibition of Smoothened

97
Q

On inside of cell in absense of hedgehog you get transcriptional __________ through the __________ of the ______ protein

A

repression, phosphorylation, Ci

98
Q

What is Ci phosphorylated by in absense of hedgehog

A

PKA, GSK3, CK1

99
Q

What does phosphorylation of Ci do

A

leads to the proteolytic processing of Ci resulting in cleavage and the small cleaved part of the Ci protein goes to the nucleus and inhibits transcription

100
Q

what happens to Patched in presence of hedgehog

A

Internalization of patched, degraded in lysosome

101
Q

What happens following degredation of Patched in presence of hedgehog

A

Patched WAS inhibiting Smoothened, now gets phosphorylated by PKA and CK1, inserted into PM
-Smoothened then recruits protein complex, inhibits Ci cleavage

102
Q

What happens when Ci cleavage is inhibited in presence of hedgehog

A

full length Ci goes to nucleus and acts as a transcriptional activator

103
Q

What can excess hedgehog signalling lead to

A

Cancer

104
Q

Is Patched activated by Ci

A

Yes, increase in Patched on cell surface inhibits further Hedgehog signaling

105
Q

Cell receptors that activate the NFkB signaling pathway in animal cells

A

-Toll-like receptors
-Tumor necrosis factor α (TNFα) and interleukin-1 (IL1) (vertebrate cytokines)

106
Q

NFκB signaling pathway with TNFα

A

-TNFα binds to rec on PM, activated IKK complex
-goes to phosphorylate IkB, IkB then ubiquinated and degraded
-IkB was inhibiting NFkB, now is free to move to nucleus and activate transcription

107
Q

Pathways that rely on phosphorylation

A

-PI3-K
-JAK/STAT
-TGFB/SMAD

108
Q

Pathways that rely on proteolysis

A

-Notch/Delta
-Wnt/ Beta Catenin
-Hedgehog
-NFkB

MCB 3010 (20 decks)

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