cell growth signaling review deck

Question 1

what is the main function of receptor tyrosine kinases

Answer 1

major positive regulators of cell division

Question 2

describe RTK with and without ligand bound

Answer 2

without ligand- monomers, low kinase activity

with ligand- dimers, high kinase activity

Question 3

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

Answer 3

TYROSINE

Question 4

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

Answer 4

adapter proteins

Question 5

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

Answer 5

SH2 or PTB

Question 6

what are the domains of GRB2?

Answer 6

SH2- binds P-tyrosine

SH3- binds SOS

Question 7

what is SOS?

Answer 7

guanine exchange factor if the Ras G protein

Question 8

what is the function of guanine exchange factor?

Answer 8

swaps GTP for GDP to active Ras G protein

Question 9

what is triggered by activation of Ras G protein?

Answer 9

Mitogen Activated Protein (MAP) Kinase

Question 10

what is the function of MAP kinase pathway?

Answer 10

regulates expression of genes on a cell for proliferation and differentiation

Question 11

What does activated Ras G Protein activate?

Answer 11

Raf kinase

Question 12

what does activated Raf kinase do?

Answer 12

phosphorylates MEK

Question 13

what does phosphorylated MEK do?

Answer 13

phosphorylates MAP kinase

Question 14

what does activated MAP kinase do?

Answer 14

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

Question 15

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

Answer 15

phosphatase will remove P

decrease receptors vis endocytosis

Question 16

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

Answer 16

assoc with pancreatic ca

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

Question 17

what is the clinical significance in mutations of RTK?

Answer 17

tumor development secondary to constitutively active receptor

Question 18

examples of RTK mutations

Answer 18

Her2-Neu in breast CA

EGF-ERB in small cell lung CA

Question 19

describe Her2-Neu

Answer 19

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

Question 20

describe EGF-ERB

Answer 20

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

Question 21

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

Answer 21

transcription factors

Question 22

what is the significance number of steps in the pathways

Answer 22

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

Question 23

what is TBF-B pathway?

Answer 23

negative regulator of cell growth

Question 24

what forms after ligand binds TGF-B receptor?

Answer 24

oligomerization occurs with 3 molecules joining, kinase activity begins

Question 25

what is phosphorylated by TGF-B kinase activity?

Answer 25

smads

Question 26

what do smads do?

Answer 26

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

Question 27

how is the signal terminated for TGF-B?

Answer 27

1- sno + ski proteins | 2- inhibitory smads

Question 28

how do son + ski proteins work?

Answer 28

bind to smads and down regulate transcription

Question 29

how do inhibitory smads work?

Answer 29

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

Question 30

what is unique about cytokine signaling?

Answer 30

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

Question 31

which kinase is assoc with cytokine receptor?

Answer 31

JAK

Question 32

what binds to the P-tyrosines of cytokine receptor?

Answer 32

SH2- domain of STAT proteins

Question 33

what is the activity of activated STAT proteins?

Answer 33

dimerize, travel into nucleus, bind DNA and activate transcription

Question 34

what does STAT stand for?

Answer 34

signal transducers of activated transcription, also implies speed

Question 35

how is the cytokine pathway terminated?

Answer 35

``` SHP1 phosphatase (specific for JAKs) SOCs proteins ```

Question 36

what are the 2 actions of SOCs proteins?

Answer 36

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

Question 37

what is the clinical significance of TGF-B?

Answer 37

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

Question 38

what is the clinical significance of cytokine receptors?

Answer 38

hematopoietic cell development and immune response

Question 39

what is xeljanz?

Answer 39

JAK inhibitor for RA treatment

Question 40

what does the WNT ligand act through?

Answer 40

frizzled receptor

Question 41

what are some attributes of the frizzled receptor?

Answer 41

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

Question 42

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

Answer 42

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

Question 43

what occurs when WNT present?

Answer 43

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

Question 44

what does b-catenin do inside nucleus?

Answer 44

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

Question 45

what is FAP?

Answer 45

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

Question 46

what can occur in breast CA with WNT pathway?

Answer 46

over expression of WNT

Question 47

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

Answer 47

cytokine receptors

Question 48

what can occur with prolonged epinephrine therapy?

Answer 48

cardiac hypertrophy secondary to activation of the MAP kinase pathway

Question 49

what occurs in the presence of b-arrestin activation?

Answer 49

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