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3 overall stages of ST
What are the 8 steps in ST?
- 1. Synthesis of molecule
- 2. Release of molecule
- 3. Secretion
- 4. Binding receptor
- 5. Activation of signal transduction machinery
- 6. Change in gene expression
- 7. Termination of cellular response
- 8. Elimination of Signal molecule
8 Major endocrine glands are:
- 1. Pineal
- 2. Pituitary
- 3. Thyroid
- 4. Thymus
- 5. Testes
- 6. Ovaries
- 7. Adrenal Gland
- 8. Pancreas
____ are the four most common intracellular secondary messangers and ___ is what they activate.
- cAMP - Protien Kinase A
- cGMP - Protien Kinase G + cation channels in rod cells
- DAG - Protien Kinase C
- IP3 - Opens Ca2+ channels in ER
Calmodulin is a ____. An example is: " ____" which is a/an ____ that (does this) ____.
- Cytosolic multipurpose switch protien that mediates the effects of Ca ions.
- Calmodulin activation of Calcinuerin which is a protien phosphatase that activates Il-2
- Il-2 stimulates t-proliferation
Cyclosporin is a ____ that works by ____ and is useful because ____.
- Immunosuppressant drug
- Forming a complex with cyclophilin which inhibits calcineurin
- Knocks down immune sys by preventing Il-2 release/activation
___ are the 7 signaling steps of the chemoattractant to cAMP
- 1. cAMP reception activates G-prot
- 2. G- prot activates Adenylate cyclase
- 3. cAMP diffuses out of cell into media
- 4. Internal cAMP inactivates external receptor
- 5. Another G-prot stimulates Phospholipase C
- 6. IP3 induces Ca2+ release
- 7. Ca2+ induces extension of psuedopodia
___ is the tertiary structure of a GCR and ___ are the parts that interact with the G-prot.
- 7 transmembrane alpha helices with 4 extracellular loops and 4 intracellular loops.
- Loops 3 and 4 (sometimes 2) interact with G-prot.
____ is a second messenger for Adenylyl cyclase.
____ is a second messanger for Phospholipase C
IP3 and DAG
___ is a second messenger for cGMP phosphodiesterase.
Phospholipase C is a/an ____ to ____ and produces _____ when activated.
- Effector protien to G-protien
- IP3 and DAG
IP3 and DAG are ____ that act on ____ to ____.
secondary messnagers that act on Ca2+ Channels (IP3) and activate Protien Kinase C (DAG) which phosphorylates various enzymes and receptors, altering thier activity.
Epo is a/an ____ that ____ specifically ancts on CFU-E which are ____.
Growth factor that stimulates differentiation in hematopoietic stem cells specifially in Colony Forming Units which are erythroid progenitor cells
Epo stimulates growth/differentation in CFU-e by ____.
Inducing trx of anti-apoptotic factors allowing the cells to RBC's
____ is the signalling pathway of Epo.
Epo (ligand) --> EpoR --> JAK --> STAT, Ras/MAP, Phospholipase C, and PI3 Kinase which lead to trx activation.
____ is the tertiary structure of a Cytokine Receptor and ____ are the conformational changes post ligand binding.
Homodimer with extracellualr ligand receptor irreversably connected to cytosolic JAK prot which is activated by dimerizing after ligand binds receptor. This causes the the JAK kinases to phosphorylate eachother on a Tyr residue at the activation lip. This increases the ability of ATP to bind and subsequent Tyr residues are phosphoylated creating docking sites for the inactive STAT monomers (trx factor - dimerizes with another STAT prot once phosphorylated = active)
RTK vs Cytokine Receptor
RTK = Different monomers which form heterodimers or homodimers when bound by a ligand. The ligand induces a loop in the cytosolic domain which interacts with the other RTK activating a protein similiar to JAK (only this is part of Cytokine)
____ is an example of an RTK in humans. There __#__ types which _____ bind to various ____.
- 4 which differentially bind to various EGF
____ are unique feartures of HER2.
It is in a preactivated state and can form heterodimers with HER 1, 3, and 4. HER3 can only signal when bound to HER2 (lacks functional kinase domain)
Why is HER2 over expression in breast cancer patients makes it worse?
HER2 make the cell sensitive to low levels of any factor of the EGF family. Levels that would not stimulate growth with normal HER2 levels.
_____ is a drug used in the treatment of cancer and works by ____.
_____ is a monoclonal antibody used against ____. This is a good drug because it is _____ to the _____ element of HER2
- Breast Cancer
RAS vs G-prot
Ras is monomeric
How is Ras activated?
- RTK binds ligand and dimerizes phosphorylating cytosolic tyrosine residue
- GRB2 (comprised of SH2 and SH3) binds Sos (SH3 specically binds Sos)
- Sos binds inactive Ras causing GDP to dissociate and GTP to bind
What is the Ras pathway?
- Ras is activated
- Recruits and binds/activates Raf - Raf is activated because the 14-3-3 protein that stabalizes Raf in its inactive form is dephosphorylated
- Hydrolysis of the Ras GTP --> GDP releases the active Raf from RasRaf phosphoryaltes MEK's activation lip
- MEK phosphoylates MAP kinases activation lip
- MAP kinase dimerizes and translocates to nucleus
- MAP kinase phosphorylates many different prot. including nuclear trx factors
What is the MAP kinase pathway?
- It is activated via Ras-Raf
- Dimerizes in cytosol
- activates p90RSK by phosphorylating its activation lip
- MAP kinase and p90RSK both then move to nucleus
- p90RSK phosphorylates/activates SRF (a trx factor)
- Nuclear MAP kinase phosphorylates/activates TCF (trx factor)
- TCF and SRF act together to stimulate trx of genes that contain SRE (enhancer region upstream of gene coding sequence) in thier promoter
What is a scaffolding protein and signaling complex?
Scaffolding Protein: large relay proteins to which other relay proteins are attached (increase signalling transduction efficiency) -groups together different proteins in pathway
Wiskott-Aldrich syndrome is ____.
A rare x-linked recessive disease that creates a missense mutation in WASP (Wiskott-Aldrich Syndrom Protein - Prot expressed in hematopoietic cells involved in signal transduction)
____, _____, and _____ are the three ways cells turn of signaling from their receptors.
- Receptor Dephosphoylation
- Receptor Degredation
- Receptor Endocytosis
How does short term Regulation of JAK2 work?
SHP1 is a heterodimer with SHP2 which binds phosphorylated tyrosine resdues on cell receptor. This activates the phosphotase on SHP1 which dephosphorylates the JAK activation lip
How does long term regulatoin of JAK2 work?
- STAT pathway induces SOCS protein
- SOCS binds phosphotyrosines on JAK and blocks other SH2 molecules - also ubiquinates it for degredation via the proteosomal pathway