Chapter 12: Signal Transduction

StudyBlue printing of Chapter 12: Signal Transduction html, body, div, span, applet, object, iframe, h1, h2, h3, h4, h5, h6, p, blockquote, pre, a, abbr, acronym, address, big, cite, code, del, dfn, em, font, img, ins, kbd, q, s, samp, small, strike, strong, sub, sup, tt, var, b, u, i, center, fieldset, form, label, legend, table, caption, tbody, tfoot, thead, tr, th, td { margin: 0; padding: 0; border: 0; outline: 0; font-size: 100%; background: transparent; } body { line-height: 1; } blockquote, q { quotes: none; } blockquote:before, blockquote:after, q:before, q:after { content: ''; content: none; } /* remember to define focus styles! */ :focus { outline: 0; } /* remember to highlight inserts somehow! */ ins { text-decoration: none; } del { text-decoration: line-through; } /* tables still need 'cellspacing="0"' in the markup */ table { border-collapse: collapse; border-spacing: 0; } /* end RESET */ .header { min-width:800px; } .logo { padding:6px 20px 2px 20px; margin:0; font-size:25px; font-weight:bold; color:#808285; position:relative; border-bottom: 1px solid #c5c5c5; } .logo-blue { color:#70adc4; } .logo-desc { font-weight:normal; font-size:19px; color:#cccccc; margin-top:50px; position:absolute; display: none; } .back-button { position:absolute; top:20px; right:20px; font-size:13px; line-height:25px; color:rgb(0,175,225); font-weight:normal; } .back-button a { color:rgb(0,175,225); } .instructions { padding:0; margin:0; width:100%; position:relative; color:rgb(100,100,100); } .step-holder { border-left:1px solid #ededed; margin-left:20px; } .steps { padding:15px 0; float:left; width:24%; border-right:1px solid #ededed; text-align:center; } .steps-01 { } .steps-02 { } .steps-03 { } .steps-04 { } .label { padding:5px 10px; } .print-button { } .print-button a { background-color:rgb(0,175,225); color:white; line-height: 19px; padding:9px 8px 5px 30px; font-size:14px; text-decoration:none; background-image: url(images/printer.png); background-repeat: no-repeat; background-position: 7px 50%; -moz-border-radius: 5px; -webkit-border-radius: 5px; } .print-button a:hover { background-color:black; } .theNote .content { width: 8.0in !important; margin: 5px auto; padding:20px; background-color:white; } .theNote .header { border-bottom: 1px dashed #C8C8C8; font-size: 17px; padding: 0 0 10px; line-height: 19px; color: #00ADE1; min-width:500px; } .theNote .body { font-size: 14px; line-height: 19px; padding: 10px 0; } .theNote{ padding:6px 0; clear:both; background-color: rgb(200,200,200); } .theNote h3{ color: rgb(100,100,100); } .theNote h1, .theNote h3{ background-color:white; padding:2px 20px; width:8.0in !important; margin: 0 auto; font-size: 15px; } .theNote h1{ padding-top: 10px; font-size: 15px; } .theNote h1:first-child{ font-size: 20px; } .theNote h3 { font-size: 14px; font-weight: normal; } #options { border: 3px double #ccc; padding: 5px 12px; margin: 10px 50px 10px 20px; float: left; } #info { border-top: 1px solid #ccc; padding-top: 5px; font-style: italic; } li { margin: 5px 10px 5px 25px; } ul li { list-style: disc; } ol li { list-style: decimal; } img { border: 0; } table { clear: both; width: 100%; border: 1px solid #c5c5c5; border-width: 1px 0; margin: 0; page-break-after: always; } table#page { page-break-after: auto; } td { text-align: center; font-size: 12px; border-bottom: 1px dashed #c5c5c5; height: 1.75in; width: 50%; padding-left: 15px; } .leftside { border-right: 1px solid #cccccc; padding: 0 15px 0 0; } .bottom td { border-bottom: none; } .clearfix { clear:both; line-height:1px; height:1px; } img { max-width:80%; max-height:150px; margin:20px; } @media print {.header { display: none; } .content .header{ display:inherit; } table { border: 1px dashed #bbb; border-width: 1px 0; } .theNote{ background-color:white; } } Signal transduction allows cells to respond to event outside the cell It begins with an extracellular cue (hormones) which influences a receptor in such a way that the receptor passes on the signal (using some other method). This signal intiates a series of events that cause a change in cellular behavior. This are can be causes by transcriptional, causing the expression of a gene, or non transcriptional (apotosis) Cellular signaling There are two general classes of receptors that intiate signal transduction membrane protein receptors at the cell surface and nuclear receptors. The first bind factors that are outside the cell and, generally, cannot access the inside of the cell. This are for the most part proteins or peptides (insulin). Receptors for these are transmembrane proteins, and must use other factors to get the signal to the nucleus and activate changes in gene transcription. Nuclear receptors are bound and activated by steroid hormones that pass through the membrane, such as testosterone or estorgen. They go into the nucleus and it is the receptor its that intiates gene transcription. Signaling mechanisms Cells can signal to themselves (autocrine) Cells can signal to adjecent/contacting cells (juxtacrine) Cells can signal to distant cells (paracrine) In cell biology endocrine refers to signally through the entire organism, though physiologists use this term as a blanket for all signaling no matter what kind Dimerization of RTKs May growth factors are transmembrane molecules, with an extracellular ligand binding domain and an intracellular tryosine kinase domain. Receptor tyrosine kinase are a major class. Receptor tyrosine kinases (RTK)s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Their ligands force dimerization. they have two domains extracellular domain and a tyrosine kinase domain. When a signal factor binds to the extracellular domain it attracts a second to dimerize with the originally bound receptor tyrosine kinase (RTKs). Phosphorylation of RTKs These receptors are always in the "active state", however it is binding and dimerizing do the two become close enough to phosphorylate one another (transphosphorylation . Phosphorylation signals other proteins to bind to the dimer. An EFG receptor (RTKs) activation intiates a signalling cascade Once phosphorylated, the two are bound by proteins containing the SH2 domains. This progresses forward binding or activating other proteins which leads to transcription of specific gene(s) NOTE!!! The SH2 ( S rc H omology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. Its presence on a protein helps that protein "find its way" to another protein by recognizing phosphorylated tyrosine on the other protein. SH2 domains typically bind a phosphorylated tyrosine residue in the context of a longer peptide motif within a target protein, and SH2 domains represent the largest class of known pTyr-recognition domains. (For more info see wiki, http://en.wikipedia.org/wiki/SH2_domain.) A benefit of this is amplification of the signal from a few receptors. In the RTK cascade phospho receptors recruit Grb2, which recruits SOS (son of sevenless). SOS is a GEF for Ras, a small GTPase, which in turn activates raf (or MAP KinaseKinaseKinase), which phosphorylates Mek (MAP KinaseKinase), which phoshphorylates ERK (MAP Kinase), which phosphorylates transcriptional activators. This kinase cascade is very important in determining how signal intensity generates cellular responses. NOTE!!!! Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor proteininvolved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene. The protein encoded by this gene binds receptors such as the epidermal growth factor receptor and contains one SH2 domain and two SH3 domains. Its two SH3 domains direct complex formation with proline-rich regions of other proteins, and its SH2 domain binds tyrosine phosphorylated sequences. (see wiki http://en.wikipedia.org/wiki/GRB2) NOTE!!! In cell signalling, Son of Sevenless ( SOS ) refers to a set of genes encoding guanine nucleotide exchange factors (GEFs) that act on the Ras subfamily of small GTPases. See figure 1 Steps in sighnaling complex Signal RTK transphosphorylation Proteins with SH2 domains (i.e Grb2) SOS (son of sevenless) RAS RAF/(MAP kinasekinasekinase) phosphorylation of Mek (map kinase kinase) phosphorylation of ERK (map Kinase) Phosphorylation of transcription activators Note that signaling in RTK pathways occurs through these signaling complexes, making signaling more efficient and preventing uncontrolled diverging of signaling pathways. Often such scaffolds are required for signal outputs. JAK-STAT Cytokine receptors with bound JAK Cytokine binds causing dimerization and trans phosphorylation Activated JAK phosphorylates the receptors Stats dock on phosphorylated intercellular domain of receptors the JAk phosphorylate the SATS STATS dissociate from the receptor and dimerize via there SH2 domain (See above) Move into the nucleus, bind to DNA and other gene regulatory proteins activate gene transcription Cascade effects on signal output Cascaded pathways cause the output of the pathway to occur once a threshold is reached, after which maximal signaling occurs. This is an on or off signaling pathway and there is generally no half-on state (Sigmoid, a high Hill’s coefficient). More direct pathways, like JAK-STAT give a more graded response (looks linear, low Hill’s coefficient). G-protein-coupled receptor The receptor is bound to a GTPase (Ga) and two other proteins in a complex. Once ligand binding occurs, Gb (a GEF) activates Ga and then Ga goes off in the plane of the membrane to intiate signaling events. Gb and Gg also move off in the membrane to intiate further signaling as well. G a can also bind and activate, when in the GTP bound state, adenyl cyclase, turning ATP into cyclic AMP. This small molecule drives further signaling. Gb/g, Ga, or both, depending on the pathway, then bind and activate phospholipase C (PLC). This an enzyme that cleaves specific lipids into the lipid tail and head group, which have secondary signaling roles. The head group, I3, floats away and causes calcium channel IP3 to to open and release calcium ions into the cytosol from calcium stores in the ER. This calcium binds and helps activate, along with the lipid tail resulting from PLC activity, protein kinase C, which initiates further signaling. This demonstrates that it is protein-protein interactions, GTPases, kinases, lipids (diacylglycerol), small molecules (IP3), and ions (calcium) that can all combine to mediate more complex signaling pathways. G a can also bind and activate, when in the GTP bound state, adenyl cyclase, turning ATP into cyclic AMP. This small molecule drives further signaling.cAMP can activate, for example, protein kinase A, or PKA. You see here that PKA is regulated by protein-protein interactions that can be released to generate activity. (figure 4) Once active, PKA can enter the nucleus and phosphorylate proteins that alter transcription. (figure 5) Protein Activation Mechanisms There are two main ways to induce a protein to start signaling. One is to activate it by making a post-translational modification in the protein or using another molecule to bind or release it. Since the activity itself changes, the conformation of the protein must change. Other proteins are always active but are only brought o the right location to exert their effect at the right time. (figure 6) NFkB Pathway An example of this is NFKB signalling. NFKB is held outside the nucleus by an interaction with IKB. This interaction is controlled by IKB phosphorylation by IKK. Once phorphorylated, NFKB is released and allowed to enter the nucleus and effect transcription Notch Signaling Pathway (Proteolytic) Yet another mechanism. This receptor (notch) is activated and becomes proteolytically cleaved. The cytosolic piece can then go into the nucleus and exert effects on gene transcription by direct interactions with nuclear proteins. figure 1 Note that signaling in RTK pathways occurs through these signaling complexes, making signaling more efficient and preventing uncontrolled diverging of signaling pathways. Often such scaffolds are required for signal outputs. Here is another signaling pathway, the JAK-STAT pathway. Here there is recruitment of signaling proteins to the receptor. Unlike RTKs, it is these same molecules that go into the nucleus and alter gene transcription. There is no cascade; the system is much more direct. G-protein coupled receptors Gprotein coupled receptors (continued) Protein Kinase A is activated by cAMP Activated PKA can effect transcription Proteins can be activated in two ways the first is to change the confirmation and so the activity allowing it to induce transcriptional changes others are always active, but are only transported into nucleus to effect transcription at a prescribed time NFkB pathway Notch Signaling