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CSF Block 5 > cell growth signaling review deck > Flashcards

cell growth signaling review deck Flashcards

1
Q

what is the main function of receptor tyrosine kinases

A

major positive regulators of cell division

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2
Q

describe RTK with and without ligand bound

A

without ligand- monomers, low kinase activity

with ligand- dimers, high kinase activity

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3
Q

what residues are phosphorylated on the cytosolic portion of the RTK?

A

TYROSINE

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4
Q

what binds to the phosphorylated tyrosine residues of the cytosolic domain of RTK?

A

adapter proteins

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5
Q

what domains of the adapter proteins will bind phosphorylated tyrosine’s?

A

SH2 or PTB

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6
Q

what are the domains of GRB2?

A

SH2- binds P-tyrosine

SH3- binds SOS

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7
Q

what is SOS?

A

guanine exchange factor if the Ras G protein

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8
Q

what is the function of guanine exchange factor?

A

swaps GTP for GDP to active Ras G protein

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9
Q

what is triggered by activation of Ras G protein?

A

Mitogen Activated Protein (MAP) Kinase

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10
Q

what is the function of MAP kinase pathway?

A

regulates expression of genes on a cell for proliferation and differentiation

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11
Q

What does activated Ras G Protein activate?

A

Raf kinase

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12
Q

what does activated Raf kinase do?

A

phosphorylates MEK

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13
Q

what does phosphorylated MEK do?

A

phosphorylates MAP kinase

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14
Q

what does activated MAP kinase do?

A

travel to nucleus, phosphorylate targets (transcription factors) that will activate genes needed to trigger cell proliferation

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15
Q

how is the MAP kinase pathway signal terminated (2)?

A

phosphatase will remove P

decrease receptors vis endocytosis

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16
Q

what is the clinical significance of mutations in Ras G protein?

A

assoc with pancreatic ca

mutated Ras can bind GTP but cannot hydrolyze, so will remain active

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17
Q

what is the clinical significance in mutations of RTK?

A

tumor development secondary to constitutively active receptor

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18
Q

examples of RTK mutations

A

Her2-Neu in breast CA

EGF-ERB in small cell lung CA

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19
Q

describe Her2-Neu

A

valine to glutamine change in the membrane domain results in dimerization in an attempt to stabilize, results in activation of kinase activity in the absence of ligand

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20
Q

describe EGF-ERB

A

ligand binding domain is deleted, kinase can be activated without ligand

21
Q

what is the target for phosphorylation in TGF-B and cytokine signaling?

A

transcription factors

22
Q

what is the significance number of steps in the pathways

A 
many steps (RTK)- increases regulation, specificity
few steps (TGF-B and cytokine)- speed
23
Q

what is TBF-B pathway?

A

negative regulator of cell growth

24
Q

what forms after ligand binds TGF-B receptor?

A

oligomerization occurs with 3 molecules joining, kinase activity begins

25
Q

what is phosphorylated by TGF-B kinase activity?

A

smads

26
Q

what do smads do?

A

once activated, smads can dimerize, travel into nucleus, bind to DNA and regulate transcription

27
Q

how is the signal terminated for TGF-B?

A

1- sno + ski proteins

2- inhibitory smads

28
Q

how do son + ski proteins work?

A

bind to smads and down regulate transcription

29
Q

how do inhibitory smads work?

A

associate with receptor, block ability of receptor to phosphorylate smad (negative feedback)

30
Q

what is unique about cytokine signaling?

A

receptor is not itself a kinase, but dose have a kinase bound

31
Q

which kinase is assoc with cytokine receptor?

A

JAK

32
Q

what binds to the P-tyrosines of cytokine receptor?

A

SH2- domain of STAT proteins

33
Q

what is the activity of activated STAT proteins?

A

dimerize, travel into nucleus, bind DNA and activate transcription

34
Q

what does STAT stand for?

A

signal transducers of activated transcription, also implies speed

35
Q

how is the cytokine pathway terminated?

A 
SHP1 phosphatase (specific for JAKs)
SOCs proteins
36
Q

what are the 2 actions of SOCs proteins?

A

1- blocks STATs from binding receptor thereby inhibiting JAK activation
2- promotes JAK degradation by recruiting ubiquitin ligases

37
Q

what is the clinical significance of TGF-B?

A

has inhibitory control of proliferation, so mutations in TGF-B receptor or smad proteins can result in tumors

38
Q

what is the clinical significance of cytokine receptors?

A

hematopoietic cell development and immune response

39
Q

what is xeljanz?

A

JAK inhibitor for RA treatment

40
Q

what does the WNT ligand act through?

A

frizzled receptor

41
Q

what are some attributes of the frizzled receptor?

A

7 trans membrane regions
assoc with LRP
regulates levels of b-catenin

42
Q

what occurs to b-catenin in the absence of WNT?

A

b-catenin is degraded in the absence of WNT by destruction complex with APC and Axin via ubiquitination

43
Q

what occurs when WNT present?

A

receptor dimerizes, axin is recruited away from destruction complex, b-catenin NOT degraded and travels into nucleus

44
Q

what does b-catenin do inside nucleus?

A

assocs with transcription factor TCF and activates genes required for cell growth

45
Q

what is FAP?

A

familial adenomatous polyposis - mutation in APC protein causes increased levels of b-catenin and increased cell turnover

46
Q

what can occur in breast CA with WNT pathway?

A

over expression of WNT

47
Q

what other type of receptors can activate Ras-MAP kinase pathway?

A

cytokine receptors

48
Q

what can occur with prolonged epinephrine therapy?

A

cardiac hypertrophy secondary to activation of the MAP kinase pathway

49
Q

what occurs in the presence of b-arrestin activation?

A

SRC-kinase recruited that can activate MAP kinase pathway as well and lead to tumor development

CSF Block 5 (18 decks)

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