White - Cell Communication 2 Flashcards
What does PKA stand for and what does it do?
Protein Kinase A; it is the downstream target of cAMP that acts on target proteins
When GPCR attaches to G-alpha-q or G-alpha-o, what is the effector in this case?
Phospholipase C instead of adenylyl cyclase
What does phospholipase C do?
Cleaves PIP2 which produces IP3 and DAG 2nd messengers
What is the function of IP3?
Releases Ca2+ from the ER by binding to an IP3-gated Ca2+ channel and triggers opening
What is the function of DAG?
Binds to protein kinase C along with Ca2+, causing a conformational change and activating PKC
What is the function of PKC?
Phosphorylates a variety of membrane and cytoplasmic substrates
Calmodulin
Protein that calcium binds to and can bind and activate other proteins to activate their functions
CaM Kinase II
Calmodulin-dependent kinase; can phosphorylate transcription factors so they can bind to DNA for transcription
Receptor Tyrosine Kinases (RTKs)
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
Growth Factors
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)
Components of RTKs
Extracellular domain, transmembrane domain, cytoplasmic domain (transmits signal through tyrosine kinase domain); adds phosphate to tyrosine on proteins
RTK Activation
- Ligand binding to this receptor causes a conformational change that induces dimerization of two receptor monomers
- Autophosphorylation occurs
- This causes the receptor to act as a scaffold to recruit other proteins to the plasma membrane
- Receptor does NOT bind to G protein but to proteins with a domain called the SH2 domain, which binds to phosphotyrosine, such as Grb2
- 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)
- Ras binds Raf which initiates MAP Kinase Cascade
What is SOS?
A GEF that exchanges GDP for GTP on Ras
Ras
First discovered human oncogene; plays crucial role in cell division and a frequent mutation in cancer
What is MAP Kinase and what does it do?
Mitogen Activated Protein Kinase; plays a role in cell proliferation
MAP Kinase Cascade
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
Signal Transduction Process
Ligand–> high affinity receptors–> intracellular signal proteins–> effector proteins–> altered gene expression
JAK-STAT Receptors
More direct route for impacting transcription
JAK-STAT Receptor Process
- Ligand binds to receptor, receptors dimerize, then bind JAKs (Janus Kinases)
2a. JAKs phosphorylate each other
2b. JAKs phosphorylate receptor - Receptor binds and phosphorylates STATs (signal transducer and activators of transcription proteins)
- STATs separate from receptors, dimerize and enters nucleus - binds to DNA and causes transcription of target genes
Erythropoeitin employs JAK-STAT to initiate signaling
R-Smad
Receptor specific Smad
Co-Smad
Common Smad
Serine-threonine Receptor and Smad Process
- Activated receptor (by phodphorylation) binds to R-Smad and phosphorylates R-Smad
- R-Smad binds to Co-Smad and moves into nucleus to impact transcription of target genes
Example: Iron metabolism through hormone called hepcidin
Hereditary Hemochromatosis
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)
DMT1
Absorbs iron into intestinal cells
Ferroportin
Moves iron out of intestinal cells and into blood
Hepcidin
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
Relationship between Hepcidin and Ferroportin
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