Description
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
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5. Course video channel at http://www.youtube.com/user/oharow/videos?view=1
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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. Cells have two ways of turning off the beta adrenergic receptor. The first involves simple dissociation of the epinephrine ligand from the receptor, leaving the receptor in the 'off' state. The second method involves phosphorylation of the receptor. The phosphorylated receptor is then bound by beta-arrestin, which inhibits the activation of G proteins.
2. Some receptors stimulate Phospholipase C. It acts on a molecule called phosphatidyl inositol (or PIP2). Cleavage of PIP2 by phospholipase C results in production of TWO second messengers. One, diacylglycerol (DAG) remains in the lipid bilayer where it stimulates Protein Kinase C. Protein Kinase C phosphorylates 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 acts to stimulate the release of calcium from intracellular storage areas.
3. 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.
4. EF Hands are important structural domains of calcium binding proteins. Calmodulin is one such protein.
5. Calmodulin binds calcium, helping to keep its free concentration 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 is CaM kinases.
6. Another signaling mechanism doesn't involve G proteins. A good example is the insulin receptor. This receptor is normally present in the membrane of a target cell in a dimer 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. In the absence of insulin binding, the subunits are non-phosphorylated and the kinase is inactive.
7. Binding of insulin 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.
8. 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. Many proteins have SH2 domains (In class I incorrectly called these SR2 domains).
9. When IRS-1binds to the insulin receptor, it gets phosphorylated on tyrosines and these tyrosines are bound by the SH2 domain of phosphatidylinositide-3-kinase, which is stimulated to phosphorylate PIP2 in the membranes, making PIP3.
10. PIP3 in the membrane is the binding target for PDK1. PDK1 phosphorylates another kinase known as Akt. Akt is NOT membrane bound and upon phosphorylation can then move through the cell, phosphorylating other proteins and activating pathways. One of the pathways it activates moves the protein known as GLUT4 to the cell surface. GLUT4 transports glucose into cells.
11. Another signaling system involves the epidermal growth factor (EGF) receptor. EGF is a small polypeptide whose action stimulates cells to divide and grow. 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.
12. The EGF receptor, like the insulin 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.
13. 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.
14. Ras is a proto-oncogene. Mutations of ras that interfere with its ability to cleave GTP to GDP can lead to uncontrolled cellular growth.
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