Principles of cell signaling - UT Southwestern

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39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 628 stimulating transcription factors, however, auxin accelerates the degradation of several specific transcriptional repressors. The auxin receptor is in fact a ubiquitin ligase complex that targets the auxin-regulated transcriptional repressors for proteolysis. F-box proteins account for all of the auxin binding activity in plant extracts. 14.29 The Wnt pathway regulates cell fate during development and other processes in the adult Key concepts • Seven transmembrane-spanning receptors may control complex differentiation programs. • Wnts are lipid-modified ligands. • Wnts signal through multiple distinct receptors. • Wnts suppress degradation of -catenin, a multifunctional transcription factor. Wnt pathways function during embryonic development and in the adult in morphogenesis, body patterning, axis formation, proliferation, and cell motility. The classical Wnt signaling mechanism was uncovered largely through studies of Drosophila and Xenopus development, as well as by analyzing genetic alterations in cancer. Wnt proteins are unusual extracellular ligands. In addition to carbohydrate, they contain covalently bound palmitate that is essential for their biological activity. Wnts transduce signals by binding to multiple distinct receptors. The most significant are members of the Frizzled family of seven-transmembrane-spanning receptors. Wnts regulate the stability of β-catenin, which either is rapidly degraded or, in response to Wnt, is stabilized to enter the nucleus and induce transcription by interacting with TCF (T-cell factor). Genes induced include c-jun, cyclin D1, and many others. The coordinated activities of the protein kinases glycogen synthase kinase 3 (GSK3) and casein kinase 1(CK1), the scaffolding proteins axin and adenomatous polyposis coli (APC), and the protein disheveled (DSH) are key to β-catenin stability. In the absence of Wnt, phosphorylation of β-catenin by CK1 and GSK3 promotes its ubiquitination and subsequent destruction by the proteasome. Axin and APC are required for phosphorylation of β-catenin by GSK3. In contrast to most seven transmembrane- spanning receptors, the Frizzled family has not yet been shown to have significant functions mediated by a heterotrimeric G protein, and G proteins may not be central to this pathway. Instead a proximal step in signaling by Frizzled involves binding to DSH, which inactivates the β-catenin destruction mechanism. Mutations that cause changes in the amounts of components of the classical pathway are common in a wide variety of cancers. Both Wnts and β-catenin may be viewed as protooncogenes. APC is a tumor suppressor and is mutated in the majority of human colorectal cancers, for example. Either too little or too much axin can also disrupt Wnt signaling, and axin, like APC, is a tumor suppressor. Wnts utilize additional signaling mechanisms. The receptor proteins Lrp5/6 (which are related to the low-density lipoprotein receptor) are Wnt receptors and also bind axin. Wnts bind to tyrosine kinase receptors to influence axon guidance and to other proteins that inhibit their function. Through DSH, Wnts can regulate the JNK MAPK pathway and Rho family G proteins to control planar cell polarity. Certain Wnts increase intracellular calcium to activate calciumdependent signaling pathways. 14.30 Diverse signaling mechanisms are regulated by protein tyrosine kinases Key concepts • Many receptor protein tyrosine kinases are activated by growth factors. • Mutations in receptor tyrosine kinases can be oncogenic. • Ligand binding promotes receptor oligomerization and autophosphorylation. • Signaling proteins bind to the phosphotyrosine residues of the activated receptor. A large group of protein tyrosine kinases are receptors that span the plasma membrane and bind extracellular ligands, as shown in FIGURE 14.34. The receptors are generally activated by growth factors whose normal physiological functions are to promote growth, proliferation, development, or maintenance of differentiated properties. This group includes receptors for insulin, epidermal growth factor (EGF), and platelet derived growth factor (PDGF). These receptors both control the activities of many other protein kinases of all families and directly regulate other classes of signaling proteins. 628 CHAPTER 14 Principles of cell signaling
39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 629 Because of their physiologic roles as growth regulators, mutations that activate receptor tyrosine kinases are often oncogenic. For example, the oncogene erbB results from the mutational loss of the extracellular ligand-binding domain of a kinase closely related to the EGF receptor. This mutation causes constitutive activation of the protein kinase domain. Point mutations that affect the transmembrane domain can also cause oncogenic activation, as is found in the EGF receptor-related neu/HER2 oncogene (see 13.8 Cell growth and proliferation are activated by growth factors). Receptor tyrosine kinases are diverse both in their extracellular ligand-binding domains and, with the exception of a conserved tyrosine protein kinase domain, their intracellular regulatory regions. These receptors usually have one membrane span per monomer but some, such as the insulin receptor, which is a disulfidebonded heterotetramer, have two. Ligand binding to receptor tyrosine kinases favors receptor oligomerization and enhances kinase activity leading to increased Tyr phosphorylation of the intracellular domain of the receptor and of associated molecules. These tyrosine-phosphorylated motifs create docking sites for additional signal transducers and adaptors. A comparison of the PDGF and insulin receptors reveals common themes and a range of behaviors of receptor tyrosine kinases. The two PDGF receptors are monomeric receptor tyrosine kinases. The insulin receptor exists in two alternatively spliced forms each of which is a heterotetramer of two and two subunits. In each case, the receptor isoforms utilize some unique signaling mechanisms. PDGF and insulin each stimulate the kinase activity of their receptors, causing oligomerization and autophosphorylation. Seven or more sites are phosphorylated on the PDGF receptor, and each phosphotyrosine residue generates a binding site for one or more SH2 domain-containing proteins as illustrated in FIGURE 14.35. The PDGF receptor binds PI 3-kinase, p190 Ras GAP, phospholipase C-, Src (which may catalyze additional Tyr phosphorylation of the receptor), and the SHP2 tyrosine phosphatase which itself binds the adaptor Grb2 (see 14.32 MAPKs are central to many signaling pathways). With the exception of Src, all of these proteins are also receptor substrates. Thus, substrates are recruited to the receptor as a consequence of specific interactions of substrate SH2 domains with receptor phosphotyrosine producing changes in activities and distributions of numerous intracellular signal EGF receptor CYTOPLASM Receptor protein tyrosine kinase families KINASE DOMAINS Insulin receptor Activation of the PDGF receptor leads to many outputs p190 RasGAP PLC-γ PDGF PDGF receptor PDGF receptors Src p85 p110 PI 3-kinase Shp2 Kinase inserts SOS FGF receptor FIGURE 14.34 The monomeric tyrosine kinase receptors consist of a globular extracellular domain that binds ligand, a single transmembrane span, and a globular intracellular region containing the protein kinase domain. The intracellular regions contain additional sequences preceding, following, and, in the case of the PDGF and FGF receptor groups, inserted into the protein kinase domain. These regions contain sites of tyrosine phosphorylation-dependent interactions. The insulin receptor is encoded by a single gene. The precursor is proteolyzed into and subunits, which are disulfide bonded to each other. Disulfide bonds also link two subunits, yielding an obligate heterotetramer. Grb2 FIGURE 14.35 PDGF binds to its receptor and induces receptor autophosphorylation. The autophosphorylated receptor binds target proteins that contain SH2 domains. 14.30 Diverse signaling mechanisms are regulated by protein tyrosine kinases 629
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