White - Cell Communication 2

Question 1

What does PKA stand for and what does it do?

Answer 1

Protein Kinase A; it is the downstream target of cAMP that acts on target proteins

Question 2

When GPCR attaches to G-alpha-q or G-alpha-o, what is the effector in this case?

Answer 2

Phospholipase C instead of adenylyl cyclase

Question 3

What does phospholipase C do?

Answer 3

Cleaves PIP2 which produces IP3 and DAG 2nd messengers

Question 4

What is the function of IP3?

Answer 4

Releases Ca2+ from the ER by binding to an IP3-gated Ca2+ channel and triggers opening

Question 5

What is the function of DAG?

Answer 5

Binds to protein kinase C along with Ca2+, causing a conformational change and activating PKC

Question 6

What is the function of PKC?

Answer 6

Phosphorylates a variety of membrane and cytoplasmic substrates

Question 7

Calmodulin

Answer 7

Protein that calcium binds to and can bind and activate other proteins to activate their functions

Question 8

CaM Kinase II

Answer 8

Calmodulin-dependent kinase; can phosphorylate transcription factors so they can bind to DNA for transcription

Question 9

Receptor Tyrosine Kinases (RTKs)

Answer 9

Play important role in signal transduction; enzyme linked receptors; enzymatic domain is in the cytoplasmic tail of the integral membrane protein; binds growth factor through extracellular domain

Question 10

Growth Factors

Answer 10

Proteins released by cells to promote growth of other cells; cause cells to proliferate and grow in cell culture

Examples: Epidermal Growth Factor (EGF), Platelet Derived Growth Factor (PDGF), Nerve Growth Factor (NGF), Fibroblast Growth Factor (FGF), Insulin-like Growth Factor 1 (IGF-1)

Question 11

Components of RTKs

Answer 11

Extracellular domain, transmembrane domain, cytoplasmic domain (transmits signal through tyrosine kinase domain); adds phosphate to tyrosine on proteins

Question 12

RTK Activation

Answer 12

1. Ligand binding to this receptor causes a conformational change that induces dimerization of two receptor monomers
2. Autophosphorylation occurs
3. This causes the receptor to act as a scaffold to recruit other proteins to the plasma membrane
4. Receptor does NOT bind to G protein but to proteins with a domain called the SH2 domain, which binds to phosphotyrosine, such as Grb2
5. Grb 2 also has SH3 domain that binds to prolines in SOS (Son of Sevenless), which then binds to Ras (small monomeric G protein - small GTPase)
6. Ras binds Raf which initiates MAP Kinase Cascade

Question 13

What is SOS?

Answer 13

A GEF that exchanges GDP for GTP on Ras

Question 14

Ras

Answer 14

First discovered human oncogene; plays crucial role in cell division and a frequent mutation in cancer

Question 15

What is MAP Kinase and what does it do?

Answer 15

Mitogen Activated Protein Kinase; plays a role in cell proliferation

Question 16

MAP Kinase Cascade

Answer 16

Ras initiates MAP kinase cascade–> MAP kinase kinase kinase (Raf)–> MAP kinase kinase (Mek)–> MAP kinase (ERK)–> nucleus–> increased gene transcription–> uncontrolled cell division (cancer) if unchecked

Question 17

Signal Transduction Process

Answer 17

Ligand–> high affinity receptors–> intracellular signal proteins–> effector proteins–> altered gene expression

Question 18

JAK-STAT Receptors

Answer 18

More direct route for impacting transcription

Question 19

JAK-STAT Receptor Process

Answer 19

1. Ligand binds to receptor, receptors dimerize, then bind JAKs (Janus Kinases)
   2a. JAKs phosphorylate each other
   2b. JAKs phosphorylate receptor
2. Receptor binds and phosphorylates STATs (signal transducer and activators of transcription proteins)
3. STATs separate from receptors, dimerize and enters nucleus - binds to DNA and causes transcription of target genes

Erythropoeitin employs JAK-STAT to initiate signaling

Question 20

R-Smad

Answer 20

Receptor specific Smad

Question 21

Co-Smad

Answer 21

Common Smad

Question 22

Serine-threonine Receptor and Smad Process

Answer 22

1. Activated receptor (by phodphorylation) binds to R-Smad and phosphorylates R-Smad
2. R-Smad binds to Co-Smad and moves into nucleus to impact transcription of target genes

Example: Iron metabolism through hormone called hepcidin

Question 23

Hereditary Hemochromatosis

Answer 23

Uncontrollable iron absorption that leads to iron overloading; toxic levels of iron get deposited in organs causing end-organ disease; treatment is challenging due to patient compliance; most common autosomal recessive disease in man (1/250)

Question 24

DMT1

Answer 24

Absorbs iron into intestinal cells

Question 25

Ferroportin

Answer 25

Moves iron out of intestinal cells and into blood

Question 26

Hepcidin

Answer 26

25 aa protein made in the liver with action in the intestine; regulator of iron homeostasis by binding to ferroportin (hepcidin receptor); hepcidin binding causes internalization of ferroportin which is destroyed by proteolysis

Question 27

Relationship between Hepcidin and Ferroportin

Answer 27

Inverse; REPLETED iron causes an increase in hepcidin expression and decreased levels of ferroportin

DEPLETED iron causes a decrease in hepcidin expression and increased levels of ferroportin