GF and Cytokine Signaling

Question 1

Which 3 aa can be phosphorylated?

Answer 1

serine, threonine, and tyrosine

Question 2

Growth factors generally signal via

Answer 2

tyrosine kinase receptors

Question 3

Tyrosine phosphorylation is

Answer 3

inducible, rare (0.05%), short-lived, and majority involved in intracellular communication

Question 4

What accounts for the short-livedness of tyrosine phosphorylation

Answer 4

high turnover of protein tyrosine phosphotases and tight regulation of tyrosine kinases

Question 5

Receptor protein tyrosine kinase

Answer 5

transmembrane with a large N-terminal extracellular domain for a ligand binding site

Question 6

Non-receptor protein tyrosine kinase

Answer 6

not transmembrane, but usually associated with the cellular membrane

Question 7

Receptor Serine threonine kinases

Answer 7

are single-pass transmembrane proteins that associate with the Smad family

Question 8

Action of receptor serene threonine kinase

Answer 8

bind ligand, causes dimerization and phosphorylation of serene and/or threonine residues of SMAD proteins

Question 9

Ligands for Receptor Serine threonine kinases

Answer 9

TGF-beta, BMP

Question 10

SMAD proteins

Answer 10

TFs that are phosphorylated at their serene or threonine residues, complexes of SMADs enter the nucleus and cause transcription of certain genes

Question 11

Serine/threonine receptor kinase plays a major role in

Answer 11

development, differentiation, anti-inflammation, immune suppression

Question 12

Tyrosine kinase receptors activation

Answer 12

ligand binds, receptors dimerize, autophosphorylate corresponding tail tyrosine residues, attracts and phosphorylates SRC: SH-2 and SH-3 adaptor proteins

Question 13

Tyrosine kinase receptor activates

Answer 13

serine/threonine protein kinases called Mitogen Activated Protein Kinase (MAPK)

Question 14

Activation of MAPK occurs through… and results in…

Answer 14

small GTPases (Ras) and results in translocation to the nucleus and phosphorylation of TFs which causes transcription of certain genes (Cyclin D)

Question 15

SH2

Answer 15

SRC homology, stretch of aa that allows the adaptor protein to bind to phosphotyrosines on receptor tails and other transient proteins

Question 16

SH3

Answer 16

SRC homology, stretch of aa that allows the adaptor protein to bind to other proteins in a phosphorylation independent fashion (proline rich sequences)

Question 17

Mutations in SRC domains (SH2/SH3)

Answer 17

affect signaling

Question 18

Ras

Answer 18

Links receptor tyrosine kinase with intracellular signaling cascade, monomeric GTPase anchroed to the cytoplasmic face of the plasma membrane

Question 19

Ras is active when

Answer 19

bound to GTP

Question 20

Ras in inactive when

Answer 20

bound to GDP

Question 21

GEF

Answer 21

due to high concentrations of GTP in the cell, Ras would be active constantly, GEF (GTP/GDP exchange factor) containing SH2/SH3 , activates Ras by exchanging GDP for GTP

Question 22

GAP

Answer 22

due to high concentrations of GTP in the cell, Ras would be active constantly, GAP (GTPase activating proteins) increase the rate of hydrolysis of bound GTP by Ras, inactivating it. Necessary to prevent constant activation!

Question 23

Neurofibrin

Answer 23

a type of GAP, product of NF-1 (neurofibromatosis)

Question 24

Ras activates

Answer 24

Serine/threonine phosphorylation cascade that mediated by MAPKinase

Question 25

Importance of Ras using a serene/threonine phosphorylation

Answer 25

Converts a short-lived signal to a long-lived signal in order for differentiation and proliferation

Question 26

When activated, MAP kinases

Answer 26

migrate to the nucleus and regulate gene transcription of genes involved in regulating cell cycle (cyclin, CDK)

Question 27

In cancer, MAPK is abnormally

Answer 27

ACTIVATED

Question 28

Can be used in orthopedic surgeries

Answer 28

BMPs

Question 29

Neurofibrin mutation will result in

Answer 29

Active Ras, triggered cell proliferation constitutively bc it activates MAPK.

Question 30

Targeted therapy

Answer 30

drugs that specifically target molecules necessary for cancer growth and progression. Many targets include EGF receptors, VEG receptors

Question 31

Autocrine production of growth factors by tumor cells

Answer 31

if tumor cell expresses growth factor and a growth factor receptor the cell can trigger its own growth

Question 32

Abnormal growth due to receptors

Answer 32

Permanent conformational change upon ligand binding, remain in active state and constitutively activate growth

Question 33

EGFR mutation (ErbB protein)

Answer 33

truncated form that lacks the extracellular ligand binding domain, but remainder of receptor remains in ACTIVATED state

Question 34

Trastuzumab (herceptin)

Answer 34

monoclonal antibody against ERBB2 (EGFR family) that blocks the receptor, preventing growth factor from binding

Question 35

Cetuximab

Answer 35

monoclonal antibody against the extracellular domain of the EGFR

Question 36

Erlotinib, Gefitinib

Answer 36

Competitive inhibitors of tyrosine kinase activity of the EGFR

Question 37

BCR-ABL

Answer 37

Mutation considered the essential transforming event in CHRONIC MYELOGENOUS LEUKEMIA where Abl (cytoplasmic tyrosine kinase) is translocated to BCR protein resulting in a fusion protein BCR-ABL

Question 38

STI 571 (Gleevec)***

Answer 38

Blocks the phosphorylation of tyrosine kinase by occupying the ATP site of the BCR-ABL fusion protein

Question 39

Ras mutations

Answer 39

point mutations that prevent GAP activity, generally a result of environmental carcinogens

Question 40

Most common Ras in lung, colon, and pancreas cancer

Answer 40

KRAS

Question 41

Most common Ras in acute myelogenous leukemia and myelodysplastic syndrome

Answer 41

NRAS

Question 42

3 Ras forms

Answer 42

NRAS, KRAS, HRAS

Question 43

Nuclear transcription factors mutations

Answer 43

mutations in negative regulatory elements of TF’s c-fos and c-jun, which allows constitutive binding to DNA and activation of DNA replication for growth and replication

Question 44

c-fos and c-jun

Answer 44

TFs that form homo and heterodimers via leucine zipper motifs that bind DNA

Question 45

Nuclear transcription factors mutations

Answer 45

overexpression of c-myc a nuclear phosphoprotein and TF causing DNA replication (translocation to another chromosome or extra copies)

Question 46

c-myc

Answer 46

nuclear phosphoprotein with a short half-life, with c-max causes DNA replication

Question 47

Burkitts lymphoma

Answer 47

a c-myc reciprocal translocation from chromosome 8 to 14 juxtaposed into H-chain genes and under H-chain control. Resulting in overexpression of c-myc

Question 48

Rheumatoid arthritis

Answer 48

Overproduction of TNF-alpha due to the immune attack on joints

Question 49

Etanercept (ENBREL)**

Answer 49

fusion protein of TNF receptor binds TNF-alpha and interferes with its action

Question 50

Infliximab (REMICADE), Adalimumab (HUMIRA)**

Answer 50

monoclonal antibody that binds to TNF-alpha

Question 51

inflammatory Cytokines bind

Answer 51

cytokine receptor and lead to the production of inflammatory effector molecules (tumor necrosis factor alpha)

Question 52

30% of women with breast cancers have amplification of

Answer 52

EGFR, resulting in increased expression of receptor proteins on the cell surface

Question 53

Post-translational modification that occurs to Ras and is critical for its function?

Answer 53

FARNESYLATION