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Cellular and Molecular Biology > Final: Ch 16 Tyrosine Kinases, Ras/MAPK > Flashcards

Final: Ch 16 Tyrosine Kinases, Ras/MAPK Flashcards

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1
Q

3 things transcription of genes is influenced by

A

Chromatin structure

Epigenetic modifications of histones

What TFs and proteins the cell contains

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2
Q

4 basic types of signal transduction pathway

A

Receptor-associated kinase (RTK/cytokine receptor)

Cytosolic kinase (GPCR)

Protein subunit dissociation

Protein cleavage

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3
Q

kinases phosphorylate what two types of kinases

A

tyrosine kinase (cancer)

serine/thr kinase

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4
Q

tyrosine kinases phosphorylate __________ as a part of activation

A

eachother

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5
Q

What 2 categories of receptor activate tyrosine kinases?

A

Receptor tyrosine kinase

Cytokine receptors

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6
Q

the target of a kinase is often a…

A

kinase

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7
Q

specifically, tyrosine kinases phosphorylate what?

A

specific tyrosine residues on target proteins

Autophosphorylate the receptor

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8
Q

what do the phosphorylated (by a tyrosine kinase) target proteins do?

A

activate one or more signaling pathways for cell proliferation, differentiation, survival, and metabolism

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9
Q

2 types of receptors that activate tyrosine kinases

A

receptor tyrosine kinases (RTK) - the tyrosine kinase is an intrinsic part of the receptor’s pp chain (encoded by same gene)

cytokine receptors - receptor and kinase bound tightly together but encoded by different genes

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10
Q

for cytokine receptors, the tightly bound ______ is known as a…

A

kinase, JAK kinase (just another kinase)

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11
Q

are tyrosine kinase receptors dimers?

A

most are monomeric, but ligand binding induces conformational change to form a dimer receptor

ex. insulin receptor is already a dimer

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12
Q

2 ways kinases are inactivated

A

by a phosphatase - remove phosphate from target protein

by endocytosis - internalize the receptor

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13
Q

what types of signaling molecule activate RTKs?

A

soluble or membrane bound peptides or hormones

ex. growth factors EGF, NGF

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14
Q

3 domains of a RTK

A

extracellular ligand-binding domain

1 transmembrane alpha helix

cytosolic domain with protein tyrosine kinase activity

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15
Q

activation lip

A

flexible domain in cytosolic side of RTK

unphosphorylated without ligand binding - blocks kinase activity (or binding of ATP like in the insulin receptor)

after ligand binding, the receptor sometimes and one kinase phosphorylates a tyrosine residue in the activation lip of the other to activate its kinase activity

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16
Q

how does the conformational change in the phosphorylated activation lip activate kinase activity?

A

reduces the Km for ATP or the substrate

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17
Q

how does activation of epidermal growth factor receptor by EGF work?

A

EGF ligand binds and forms an asymmetric kinase dimer

the activator kinase binds the juxtamembrane segment of the receiver kinase

this causes a conformational change that removes the activation lip from the kinase active site of the receiver

the active kinase phosphorylates tyrosine residues in the receptor

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18
Q

_ RTSs participate in signaling by the members of the ___ family of signaling molecules

A

4, EGF

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19
Q

in humans, the _ members of the ___ family are…

A

4, HER (human epidermal growth factor receptor)

HER 1-4

HER1 - homodimerization

HER2- heterodimerization

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20
Q

Gene amplification of HER2

A

Error in DNA replication makes multiple copies of HER2

HER2 makes cells more sensitive to EGF

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21
Q

amplification of the HER2 gene

A

25% of breast cancer - overexpression of HER2 protein in tumor cells

makes the tumor cells sensitive to growth my low levels of any member of the EGF family

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22
Q

an effective therapy for HER2 overexpression

A

monoclonal antibodies for the HER2 protein

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23
Q

cytokines

A

small, secreting signaling molecules that control growth and differentiation of specific cells

ex. interleukins (proliferation and functioning of T cells and Ab producing B cells) –> TNF-alpha

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24
Q

prolactin

A

a cytokine that during pregnancy, causes the epithelial cells lining the mammary gland ducts to differentiate into acinar cells that produce milk

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25
Q

interferons

A

cytokines that are secreted after viral infection

act on nearby cells to induce enzymes that make the cells resistant to viral infection

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26
Q

many cytokines induce formation of important types of _____ cells

A

blood

ex. erythropoietin (Epo) - triggers production of RBC

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27
Q

binding of a cytokine to its receptor activates a tightly bound ___ protein tyrosine kinase

A

JAK

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28
Q

all cytokines evolved from a common ancestral protein and have a similar tertiary structure consisting of…

A

4 long alpha helices folded together

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29
Q

cytokine receptors do not posses _______ enzymatic activity

A

intrinsic - instead a JAK kinase is tightly bound to the cytosolic domain

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30
Q

JAK stands for

A

just another kinase

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31
Q

the 4 members of the JAK kinase family 3 domains…

A

N-terminal receptor binding domain

C-terminal kinase domain (poorly active)

middle domain that regulates kinase activity

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32
Q

how are JAK kinases activated?

A

just like in RTKs - ligand binding induces conformational change to form a dimer where the JAKs are close together so they can phosphorylate each other

this phosphorylation enhances ATP/substrate affinity to increase kinase activity

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33
Q

what purpose do the phosphorylated tyrosine residues serve?

A

binding sites for proteins that have phosphotyrosine binding domains

ex. SH2 domain

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34
Q

what determines which phosphotyrosine an SH2 will bind?

A

variations in the hydrophobic pocket In the SH2 domain

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35
Q

phosphotyrosine binding domain (PTB)

A

found on multidocking proteins

Bind phosphorylated tyrosines on the receptor

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36
Q

multidocking protein

A

serve as docking sites for multiple signal transduction proteins

ex. IRS-1 (insulin receptor substrate) is phosphorylated by the receptor and the tyrosines (on IRS-1) serve as docking sites for SH2-containing signaling proteins

37
Q

JAK kinases activate ____ transcription factors

A

STAT TFs

38
Q

3 domains of STAT

A

N-terminal DNA binding domain

SH2 domain that binds phosphotyrosines in a cytokine’s cytosolic domain

C-terminal domain with a critical tyrosine residue

39
Q

how does JAK-STAT work?

A

SH2 domain on STAT binds the activated cytokine receptor at a phosphotyrosine

JAK kinase phosphorylates STAT’s C-terminal tyrosine

STAT dissociates from the receptor and dimerizea, exposing a nuclear-localization signal

the STAT dimer moves into the nucleus and binds specific enhancers to alter gene expression

40
Q

are the genes available to be activated by any STAT different?

A

yes

in mammary glands, STAT5 induces transcription of genes encoding milk proteins

when STAT5 is activated in erythroid progenitor cells, it induces transcription of the bcl-xl gene that prevents apoptosis

41
Q

prolonged treatment of cells with ligand often _____ the number of available cell-surface receptors so there is a less robust response to ligand than at the beginning of treatment

A

reduces (desensitization)

42
Q

desensitization example HER1/EGF

A

in absence of EGF, HER1 receptors are long lived (receptor-mediated endocytosis occurs at a slow rate)

after EGF binding, endocytosis of HER1 is increased and only a few receptors return to the membrane, most are degraded in lysosomes

43
Q

do HER1 mutants that lack kinase activity undergo accelerated endocytosis in the presence of ligand?

A

no

perhaps b/c activation of kinase activity in normal HER1 induces conformational change that exposes a sorting motif that signals endocytosis

44
Q

can internalized receptors signal from within endosomes before their degradation?

A

yes

evidence: binding signaling proteins like Grb-2 and Sos

45
Q

2 things that can happen to internalized receptors

A

returned to cell membrane

degraded in lysosomes

46
Q

ubiquitination

A

addition of the small protein ubiquitin to a lysine in a protein signals it for degradation

enzyme c-Cbl does this

47
Q

SHP1

A

phosphatase that negatively regulates signaling from cytokine receptors

inactivates JAK protein by binding to active receptor

has 2 SH2 domains

48
Q

SHP1 in inactive state

A

one SH2 domain of SHP binds the catalytic site so it is inactive

49
Q

SHP1 in active state

A

The blocking SH2 domain binds a phosphotyrosine in the active receptor

Catalytic site placed near phosphate in JAK activation lip and removes

50
Q

SOCS proteins

A

terminate signaling from cytokine receptors by negative regulation

SH2 domain binds activated receptor to block binding of other SH2 containing proteins (competitive inhibition)

51
Q

SOCS-1 mechanism

A

binds critical phosphotyrosine in activation lip of activated JAK2 kinase

52
Q

SOCS box

A

domain that recruits ubiquitin ligases

Ubiquitin is a signal for degradation in proteasomes

53
Q

almost all RTK and cytokine receptors activate which pathway

A

Ras/MAP

54
Q

Ras protein

A

small monomeric G protein

member of the GTPase superfamily of switch proteins

55
Q

what does activated Ras promote at the membrane

A

formation of signal transduction complexes containing 3 sequentially acting protein kinases (kinase cascade)

The kinase cascade activates MAP kinases

56
Q

what do members of the MAP kinase family do

A

translocate into the nucleus and phosphorylate many proteins

ex. TFs that regulate expression of proteins for the cell cycle

57
Q

Ras activation is accelerated by

A

guanine nucleotide factor (GEF)

binds the Ras*GDP complex to cause dissociation of GDP

58
Q

what deactivates Ras

A

GTPase activating protein (GAP)

catalyzes hydrolysis of GTP to GDP to inactivate Ras (Ras has a low intrinsic hydrolysis rate)

59
Q

does Ras operate downstream of most RTKs and cytokine receptors?

A

yes

60
Q

the compound eye of the fly is composed of 800 individual eyes called _______

A

ommatidia

each ommatidium consists of 22 cells, 8 of which are photosensitive neurons called retinula or R cells (R1-R8)

61
Q

Sevenless (Sev)

A

an RTK that regulates development of R7 cell in an ommatidium

62
Q

flies with mutant Sev gene

A

R7 cell does not form, flies can’t see UV light

63
Q

Boss (bride of Sevenless)

A

protein expressed on the surface of R8 cells - is the ligand for the Sev RTK on the surface of the R7 precursor cell

no Boss, no R7 cells

64
Q

fruit fly experiment with Sev + Ras

A

temperature sensitive Sev mutant formed R7 cells at an intermediate temp

2nd mutation in 1/3 other important proteins in the pathway produced no R7 cells (SH2 adapter, Sos-a GEF, Ras)

65
Q

always active Ras in Sev mutant fly

A

produces R7 cells even though no Sev

proves that activation of Ras is a critical step in intracellular signaling by most if not all RTKs and cytokine receptors

66
Q

RTKs and JAK kinases are linked to Ras by _______ proteins

A

adapter - serve as a link, not catalytic

GRB2 - links activated receptor (SH2) and SoS (SH3)

SoS (Son of Sevenless) - a GEF that speeds up GTP binding to Ras

67
Q

SoS (Son of Sevenless)

A

a guanine nucleotide exchange protein (GEF) that catalyzes conversion of inactive GDP-Ras to active GTP-Ras

68
Q

binding of SoS to inactive Ras causes a conformational change that triggers..

A

dissociation of GDP so GTP can bind and activate Ras

69
Q

signals pass from activated Ras to a cascade of protein _______, ending with ____ _______

A

kinases, MAP kinase

70
Q

mitogen

A

a ligand that stimulates growth and division (cell cycle)

71
Q

MAP kinase (MAPK mitogen activated protein kinase)

A

cytosolic kinase

gets phosphorylated by MEK and activated, then amplifies the signal by phosphorylating nuclear TFs

72
Q

Melanoma

A

Always active B-Raf stimulates MEK/MAP to make skin cancer

73
Q

Ras/MAPK pathway

A

active Ras*GTP binds N-terminal domain of Raf kinase

hydrolysis of RasGTP to RasGDP releases active Raf

Raf phosphorylates MEK which phosphorylates MAP

MAP phosphorylates nuclear TFs

74
Q

mutant Raf kinase without N-terminal regulatory domain

A

always active and induce cultured cells to proliferate in absence of stimulation by growth factors

also tumor cells

75
Q

does MAPK dimerize?

A

yes, after phosphorylation a conformational change occurs and it dimerizes

the dimer is translocated into the nucleus where it phosphorylates TFs

76
Q

what does quiescent mean

A

non-growing

77
Q

early response genes

A

induced well before cells enter S phase

ex. one of these genes encodes the TF c-Fos

78
Q

c-Fos

A

TF that induces expression of many genes encoding proteins required for cells to move through the cell cycle

79
Q

most RTKs that find growth factors utilize the MAPK pathway to activate genes encoding proteins like _-__, which propel the cell through the cell cycle

A

c-Fos (a TF)

80
Q

the enhancer that regulates the c-Fos gene contains a _______ _______ ______

A

serum response element - an enhanced that binds many TFs

81
Q

MAPK induces transcription of the c-Fos gene by direct activation of which TF, and indirect activation of another TF

A

direct: ternary complex factor
indirect: serum response factor

82
Q

association of phosphorylated ternary complex factor with two molecules of phosphorylated serum response factor forms… I

A

an active trimeric factor that activates gene transcription

83
Q

_____ transmit signals to MAPK in yeast mating pathways

A

GPCR

G-betagamma triggers a kinase cascade like Ras/MAPK cascade

84
Q

_____ proteins separate multiple MAPK pathways

A

scaffold

allow the kinases of one pathway to interact with one another, but not with kinases from other pathways

ex. Ksr (kinase suppressor of Ras) binds MEK and MAPK

85
Q

basic idea of scaffold proteins

A

coordinates responses by organizing free floating proteins

ex. MAPK on scaffold activated in Ras/MAPK pathway

MAPK-P can enter nucleus and phosphorylate TFs

86
Q

mitogens up…

A

cell proliferation

cell cycle

active in cancer

87
Q

weird note about nutrients for animal cells

A

90% defined medium, 10% fetal calf serum (growth factors)

eliminate 10% = serum starved cells

look at signaling pathways activated when it is added back

88
Q

Dominant-negative mutation

A

A loss of function in cells with wild-type copies

Mutant prevents normal protein from functioning

Cellular and Molecular Biology (34 decks)

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