Shashiva 8 Phosphoinositides

nibbs06's version from 2016-04-16 23:10


Question Answer
True or False. Phosphoinositides are insoluble and membrane bound. True
Where do all phosphoinositides originate from? Mother of phosphoinositide (phosphatidylinositol)
What are the enzymes that make phosphoinositides? Kinases (add a phosphate in the expense of an ATP) & Phosphatases (remove phosphate)
Membrane trafficking governed by phosphoinositides has 2 methods of movementInternalization (endocytosis) & Exocytosis
What is the purpose of membrane trafficking? Bring proteins and lipids inside the cell and distribute within the cell from the ER
What allows the recycling of membrane vesicle? Early endosome via binding to the receptors on the plasma membrane
Which PI’s are involved in the plasma membrane with regard to membrane trafficking? PI(4)P or PI(5)P are required to make PI(4,5)P2
What is the enzyme that is responsible for converting PI(4)P to PI(4,5)P2? What reverses the process to inactivate it? PI5K. Synaptojanin I and II (phosphatase) reverse the inactivation process
What is the main protein for the formation of endosomal vesicles? & What allows binding of the PI(4,5)P2 to the membrane (binding domain)? Clathrin. Clathrin and Adapter protein
What does the dephosphorylation of synaptojanin do to PI(4,5)P2? What is another phosphatase that breaks down PI(4,5)P2? Detaches the vesicle that was formed by PIP5K, ARF, PIP2 binding domain, clathrin, and adapter. OCRL1 (leads to Lowe syndrome – brain defects and metabolics).
What is the phenotype observed in KO of PI kinases in mice? Myocardial developmental defects
Where are PI(3)P and PI(3,5)P2 found? Where does PI(3,5)P2 originate from? Endosome, originates from PI(3)P
What enzyme converts PI(3)P to PI(3,5)P2? PIKfyve (single copy gene). Includes a kinase and phosphatase
What is the difference between global and tissue specific knockout? Tissue specific (conditional KO) – mouse carries the gene that is going to be knocked out
What happens when PIKfyve is knocked out in skeletal muscle (an enzyme in PI(3,5)P2 (in endosome))? Misbalance of glucose homeostasis, Muscle becomes insulin resistant & Cannot metabolize glucose.
What happens when SAC3 phosphatase is KO in mice (an enzyme in PI(3,5)P2 (in endosome))? & What is the disease associated with this that affects on mutation (heterozygous)? Massive neurodegeneration & Charcot-Maire-Tooth-4J
What is the enzyme that makes PIP3 from PI(4,5)P2? PI3 Kinase (many meetings dedicated to this kinase – critical)
What is the enzyme that is responsible for converting PI(4,5)P2 to PI(3,4,5)P3? What reverses the process to inactivate it? PI3K Class IA (Class IA includes p110 or p85) & PTEN (phosphatase)
What is the first downstream signaling that recognizes PIP3 activation? AKT
What happens if we inactivate PTEN? Increase in cell proliferation that allows for PIP3 to accumulate
What human cancers are prevalent when PI3-kinase/AKT(PKB) pathway is dysregulated? Ovarian, cervical, breast, colon, bladder, brain , leukemia, melanoma
What is the mutated form of the EGF receptor? What does it do? ErbB. It stays on plasma membrane and signals through PIP3 and AKT all the time (cancerous)
What does mutation of RAS cause? Cancer
Where do all inhibitors stem from? Wortmannin
What defects are observed in humans and mice when PIK3 is KO, respectively? Humans – cancer & Mice – embryonal lethality
What defects are observed in humans and mice when PTEN is KO? Humans – macrocephaly/autism, cancer & Mice – embryonic lethality, tumorigenesis
When does GLUT4 fuse with the plasma membrane? What is its function? & What happens when the cell is insulin resistant? When it is stimulated by insulin it Bring glucose molecules inside the cell. GLUT4 transporters will remain in endosomes and not fuse with plasma membrane to boost glucose uptake in the cell (diabetes) – through inactivation of AKT.
What is the process after insulin has activated the receptor in regard to GLUT4 translocation? Phosphorylation – recognized by the regulatory subunit of the PI3K – allows p110 to become more active – PIP3 active – activates AKT – allows for GLUT4 to move to plasma membrane
What occurs when phosphatase SKIP and SHIP have defects? SKIP – increased insulin sensitivity – induced obesity. SHIP – increased insulin sensitivity
In humans, PIP3 acts on the plasma membrane and activates Oncogenic pathway & the Insulin pathway
**Inhibition of PIP3 in cancer patients- would it reduce insulin sensitivity? If yes, why? Yes, AKT will not be activated and thus GLUT4 will not move to the plasma membrane to boost glucose uptake. “Rapid membrane reshaping through phosphoinositide (PI) synthesis/degradation is essential for vital cellular processes. Dysfunction of the enzymes involved in PI metabolism is associated with many fatal diseases”