1. Contact me at kgahern@davincipress.com / Friend me on Facebook (kevin.g.ahern) 2. Download my free biochemistry book at http://biochem.science.oregonstate.edu/biochemistry-free-and-easy 3. Take my free iTunes U course at https://itunes.apple.com/us/course/biochemistry/id556410409 4. Check out my free book for pre-meds at http://biochem.science.oregonstate.edu/biochemistry-free-and-easy 5. Course video channel at http://www.youtube.com/user/oharow/videos?view=1 6. Check out all of my free workshops at http://www.youtube.com/playlist?list=PLlnFrNM93wqyTiCLZKehU1Tp8rNmnOWYB&feature;=view_all 7. Check out my Metabolic Melodies at http://www.davincipress.com/metabmelodies.html 8. My courses can be taken for credit (wherever you live) via OSU's ecampus. For details, see http://ecampus.oregonstate.edu/soc/ecatalog/ecourselist.htm?termcode=all&subject;=BB 9. Course materials at http://oregonstate.edu/instruct/bb450 Signaling Highlights 1. Other receptors involved in signal transduction (signaling) act in different ways. For example, some receptors stimulate the activity of the enzyme Phospholipase C. This enzyme acts on a membranous molecule called phosphatidyl inositol (or PIP2). Cleavage of PIP2 by phospholipase C results in production of TWO second messengers - 1) diacylglycerol (DAG) remains near or in the lipid bilayer where it stimulates another kinase, Protein Kinase C. Protein Kinase C acts to phosphorylate numerous proteins/enyzmes to activate/inactivate them. The other second messenger produced by phospholipase C cleavage is inositol 1,4,5 triphosphate (IP3). IP3 is soluble in the cytoplasm and it acts to stimulate the release of calcium from intracellular storage areas. 2. Calcium Is a kind of 'third' messenger in the process of signaling. Cells normally must keep the concentration of the ion low so as to prevent it from binding to proteins and precipitating DNA. Calcium is essential for muscular contraction. 3. EF Hands are important structural domains of calcium binding proteins. Calmodulin is one such protein. 4. Calmodulin binds calcium, helping to keep its concentration relatively low. Upon binding calcium, calmodulin changes shape and this change in shape allows it to bind to other proteins that it wouldn't otherwise be able to bind to. One class of these are the CaM kinases that are stimulated to phosphorylate proteins when calmodulin binds. 5. Another signaling mechanism is mediated directly through receptors and doesn't involve G proteins. The insulin receptor is normally present in the membrane of a target cell in a dimeric form and consists of two extracellular alpha subunits and two intracellular beta subunits. The beta subunits contain the active site of the enzyme, a tyrosine kinase. 6. Binding of insulin by the insulin receptor moves the units of the dimer closer together. This, in turn, causes the two tyrosine kinase sites to phosphorylate tyrosine residues on the opposite one, activating it. The two kinases then phosphorylate tyrosines at other places on each beta subunit. 7. The phosphorylated tyrosines on the insulin receptor are binding targets for proteins known as insulin receptor substrates (IRS-1). The protein contains a common domain, called SH2 that recognizes and binds phosphorylated tyrosines. 8. When IRS-1binds to the insulin receptor, it gets phosphorylated on tyrosines, as well, and these phosphorylated tyrosines are bound by the SH2 domain of an enzyme known as phosphatidylinositide-3-kinase. When phosphatidylinositide-3-kinase binds to the IRS protein, it is stimulated to phosphorylate PIP2 in the membranes, making PIP3. 9. PIP3 in the membrane is the binding target for PDK1 (PIP3-dependent protein kinase). PDK1 is thus activated in this way and it phosphorylates another kinase known as Akt. Akt is NOT membrane bound and upon phosphorylation is activated. It can then move through the cell, phosphorylated other proteins and activating pathways. One of the pathways it activates results in the movement of the protein known as GLUT4 to the cell surface. GLUT4 is a glucose transport protein that transports glucose into cells. 9. Another signaling system is that going through the epidermal growth factor (EGF) receptor. The EGF receptor that it binds to exists in cell membranes as a MONOMER. Binding of EGF to the monomeric receptor causes the receptor to dimerize. 10. The EGF receptor has an intracellular domain that is a tyrosine kinase. Dimerization of the receptor causes the carboxy-terminal portion of the receptor to become phosphorylated at tyrosines. 11. Genes in which mutations can happen that lead to uncontrollable growth are known as oncogenes. The unmutated forms of these genes perform important signaling or control functions. These unmutated genes are known as proto-oncogenes. 12. Ras is a proto-oncogene. Mutations of ras that interfere with its ability to cleave GTP to GDPcan lead to uncontrolled cellular growth.

• published: 14 Nov 2013
• views: 23