Abnormal Growth Factor/Cytokine Signaling

Question 1

AA that can be phosphorylated

Answer 1

Tyr
Ser
Thr

Question 2

Major function of Tyr phosphorylation

Answer 2

Intracellular communication

Question 3

Are nonreceptor protein kinases transmembrane?

Answer 3

No, they are just associated w/ membranes

Question 4

Are receptor Ser and Thr kinases transmembrane?

Answer 4

Yes

. Associate w/ proteins from Smad family

Question 5

Receptor Ser/Thr kinase characteristics

Answer 5

. Single-pass transmembrane proteins that become kinases when they bind their ligand
. Attach phosphate groups to Ser or Thr residues of target proteins
. Ligands: TGF-beta, bone morphogenetic proteins (BMPs)

Question 6

Mechanism of receptor Ser/Thr kinases

Answer 6

. Ligand binds to extracellular portion of receptor
. Dimerizes and phosphorylates Smad proteins in the cytoplasm
. Complexes of Smad then bind to DNA and promote transcription of key genes

Question 7

Regulatory SMADs

Answer 7

. Involved in direct signaling by growth factors
. SMAD4 is co-Smad that partners w/ R-SMAD
. SMAD6 and 7 work to suppress R-
SMAD

Question 8

Significance of Ser/Thr receptor kinases

Answer 8

. Role in development, differentiation, anti-inflammation, immune suppression
. BMPs used in orthopedic applications
. TGF-beta inhibits cell cycle progression in epithelial cells (inhibits c-myc or activate CDK inhibitor that opposes c-myc)

Question 9

MAPK pathway

Answer 9

. MAPKs activated by interaction w/ small GTPases or other protein kinases that connect MAPK to cell surface receptors or external stimuli
. Pathway ends in nucleus where Ser/Thr kinases activate transcription factors

Question 10

SH2/3 domains in proteins

Answer 10

. Motifs of AA that allow them to recognize and bind to specific proteins
. SH2 recognize phosphorylated Tyr, enable proteins that contain them to bind to activated RTK or other signaling proteins that are transiently phosphorylated on Tyr
. SH# interacts w/ other proteins in phosphorylation independent sequence specific fashion (bind Pro-rich sequences)

Question 11

Ras proteins

Answer 11

. Link in intracellular signaling cascades activated by RTKs
. In superfamily of monomeric GTPases
. Anchored to cytoplasmic face of plasma membrane
. Function as switches (active w GTP, not w/ GDP)

Question 12

Things that regulate Ras

Answer 12

. GDP/GTP exchangers: activate Ras by exchanging GDP for GTP

. GTPase: inactivates Ras by inc. rate of hydrolysis of bound GTP

Question 13

Neurofibrin

Answer 13

. Type of GTPase activating proteins

. Product of gene NF-1

Question 14

Autocrine production of GFs by tumor cells

Answer 14

Some tumor cells express both a growth factor and corresponding receptor
. Stimulates own growth

Question 15

Epidermal growth factor receptor (EGF) mutation

Answer 15

. Produces truncated form of EGF receptor w/ deletion of extracellular amino terminal end
. Produces protein that contains transmembrane protein and cytoplasmic Tyr kinase domain of EGF receptor
. Lacks ligand-binding domain but retains transducing domains in activated state

Question 16

Trastuzumab (Herceptin)

Answer 16

. Monoclonal antibody against ERBB2 (Her2/neu)

Question 17

Cetuximab

Answer 17

Monoclonal antibody against extracellular domain of EGF receptor

Question 18

Erlotinib and Gefitinib

Answer 18

Competitive inhibitors of Tyr kinase activity of EGF receptor

Question 19

Gleevac

Answer 19

. Deregulated Tyr kinase activity of BCR-ABL responsible for CML
. Gleevas blocks phosphorylation rxn of Tyr kinases by occupying ATP binding site of kinase

Question 20

mutations in RAS proteins that allow of constitutive activation of signaling pathways

Answer 20

. Point mutations prevent Ras proteins from being inactivated by GAP

Question 21

Mutations in HRAS proteins are assoc. w/ ____

Answer 21

Exposure to environmental carcinogens

Question 22

Mutations in KRAS are found in ___

Answer 22

Carcinomas of lung, colon, and pancreas

Question 23

NRAS mutations seen in ____

Answer 23

AML and myelodysplastic syndromes

Question 24

C-fos and C-jun

Answer 24

. Encode TFs that form homo and heterosexual-dimers via Leu zipper motifs
. Normally expressed in response to GFs, part of cascade for DNA replication
. Oncogenic forms carry mutations that lead to loss of negative regulatory elements so they become constitutively active

Question 25

C-myc

Answer 25

. Encodes nuclear phosphoprotein that acts as TF in conjunction w/ another factor c-max
. Inc. just prior to DNA replication
. Has short half0life
. In cancers it is amplified or is translocated to another chromosome and overexpresses a gene that should be made in regular amounts

Question 26

Burkitts lymphoma

Answer 26

. Fast growing tumor of B-lymphocytes
. Reciprocal translocation of chromosome 8 and 14
. C-myc gene normally on 8 but is translocated to 14 that has genes coding for H-chains
. C-myc now is regulated by H-chain genes and overexpresses c-myc
. No mutation in DNA sequence of myc gene but has inappropriate expression

Question 27

RA treatment with TNF inhibition

Answer 27

. Immune attack produces tumor necrosis factor (TNF)
. TNF receptor fusion protein called etanercept treats RA by fusing w/ TNF and inferring w/ its action
. Infliximab binds to TNF-alpha and treats RA
. Humira also binds to TNF-alpha