Principles of cell signaling - UT Southwestern

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39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 634 Crk ECM Crk Src CAS CYTOPLASM FAK SOS Integrin signaling INTEGRINS Paxillin Talin Vinculin Grb2 Actin filament ILK p85 PI 3- Kinase p110 Vinculin Tensin Talin FIGURE 14.40 Integrins bind to an array of cytoplasmic proteins to regulate the cytoskeleton and intracellular signaling pathways. The associated cytoskeletal elements include actin filaments and focal adhesion proteins -actinin, vinculin, paxillin, and talin. Signaling molecules include the focal adhesion kinase FAK; the adaptors Cas, Crk and Grb2; Src and CSK (see 14.31 Src family protein kinases cooperate with receptor protein tyrosine kinases), PI 3-kinase (see 14.16 Lipids and lipid-derived compounds are signaling molecules); and the Ras exchange factor SOS. Stimulation of GTP binding of Ras by SOS leads to activation of the MAPK pathway (see 14.32 MAPKs are central to many signaling pathways). Talin and α-actinin are among cytoskeletal proteins that interact directly with certain integrin subunits. These cytoskeletal proteins link integrins to complex cytoskeletal structures known as focal adhesions. Focal adhesions connect the cytoskeleton to signal transduction cascades that communicate states of cellular attachment to the regulation of cellular responses. Focal adhesion complexes contain the focal adhesion kinase FAK, which is activated by integrin ligation. Autophosphorylation of FAK recruits signaling proteins containing SH2 domains, especially the p85 subunit of PI 3-kinase and Src family protein kinases. The signaling molecules associated with the integrin-bound cytoskeletal proteins, whether focal adhesions or other structural complexes, mediate the diverse actions of integrins. The association of cytoskeletal proteins with integrin receptors also causes functional changes to the receptors. Signals that act over a distance, such as hormones, can also employ nonreceptor tyrosine kinases to transmit their message inside a cell. Growth hormone (GH) is a protein hormone secreted by the anterior pituitary gland that regulates bone growth, fat metabolism, and other cellular growth phenomena. Absence of growth hormone results in short stature, whereas hypersecretion causes acromegaly, a form of gigantism. The GH receptor is a member of the cytokine receptor family, which includes receptors for prolactin, erythropoietin, leptin, and interleukins. All these receptors display similar biochemical functions, such as association with members of the JAK/TYK family of protein tyrosine kinases, but select for different but overlapping sets of cytoplasmic signaling proteins. Signal transduction by the GH receptor provides a model for receptors that lack enzymatic function and act as agonist-promoted scaffolds for intracellular signaling proteins. FIGURE 14.41 shows the structure of growth hormone bound to the extracellular domain of its receptor. The majority of binding energy comes from only a small number of residues in the binding interface. Inside the cell, signaling by the GH receptor depends significantly on its association with the cytoplasmic tyrosine protein kinase Janus kinase 2 (JAK2). FIGURE 14.42 shows that JAK2 binds to a proline-rich region of the receptor. Ligand binding induces receptor dimerization, which then promotes activation of JAK2 through intermolecular autophosphorylation. GH signaling is thus mediated primarily by inducing Tyr phosphorylation. In addition to JAK2 autophosphorylation, the receptor itself becomes Tyr phosphorylated. As is true for receptor tyrosine kinases, Tyr phosphorylation of the growth hormone receptor creates binding sites for signaling proteins that contain phosphotyrosine-binding domains. Primary targets are transcription factors known as signal transducers and activators of transcription, or STATs. STATs contain SH2 domains and bind Tyr-phosphorylated motifs on the growth hormone receptor. While receptor bound, STATs are Tyr phosphorylated by JAK2 and then released to travel to the nucleus to mediate changes in transcription. The growth hormone receptor and the associated JAK2 also activate other signaling pathways. For example, the adaptor Shc is Tyr phosphorylated by JAK2. Engagement of Shc leads to activation of Ras and the ERK1/2 MAPK pathway. Adaptors specialized for insulin-signaling pathways, insulin receptor substrates (IRS) 1, 2, and 3, are also growth hormone targets, perhaps reflecting the ability of growth hormone to induce certain insulin-like metabolic actions. Feedback circuits are also engaged during GH signaling. The growth hormone receptor complex binds the adaptor SH2-B, which has a 634 CHAPTER 14 Principles of cell signaling
39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 635 Growth hormone structure Growth hormone signaling is transduced by JAK2 Growth hormone receptor hGH Growth hormone Dimerization JAK2 JAK2 ΔΔG (kcal/mol) > 1.5 0.5 to 1.5 -0.5 to 0.5 < -0.5 untested CYTOPLASM JAK2s bind and phosphorylate receptor STAT STAT STATs bind and are phosphorylated FIGURE 14.41 Proteins often interact over a large surface area. Growth hormone binding to its receptor is an example of the energy of binding coming primarily from a small number of the contacts between the two proteins, creating an interaction hot spot. The complex of growth hormone bound to the growth hormone receptor-binding domain determined by crystallography has been peeled apart in this figure to show the binding energy associated with residues in the binding interface from each protein determined by mutagenesis and binding studies. Fewer than half of the residues in the interface contribute the majority of binding energy. Reproduced with permission from T. Clackson and J. A. Wells. 1995. Science. 267: 383–386. © AAAS. Photos courtesy of Tim Clackson, ARIAD Pharmaceuticals, Inc. NUCLEUS Phosphorylated STATs bind DNA FIGURE 14.42 The growth hormone receptor binds to JAK2. Many GH signals are mediated by Tyr phosphorylation of the receptor by JAK2, which creates binding sites for signaling molecules with SH2 domains, notably STATs. STATs then enter the nucleus to cause changes in gene transcription. stimulatory effect on growth hormone signaling. On the other hand, suppressors of cytokine signaling (SOCS proteins) are among the genes whose transcription is induced by growth hormone. As the name indicates, SOCS proteins inhibit cytokine signaling in some if not all cases by inhibiting the activity of JAK2. SOCS proteins contain an SH2 domain that facilitates their binding either to phosphorylated JAK2 or cytokine receptors. The mechanism of signaling inhibition may differ among SOCS proteins because some require the GH receptor to interfere with JAK2 signaling. SOCS-1, on the other hand, binds directly to the JAK2 activation loop and does not require a receptor to inhibit JAK2 activity. This mechanism may be particularly important in GH signaling because, in contrast to the ligand-induced down regulation mechanisms controlling many receptors, the GH receptor is degraded in a ligand-independent manner. Receptors for cytokines also act by recruiting tyrosine kinases. The cytokines—signaling proteins that modulate inflammation and cell growth and differentiation—include interleukins, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, cardiotrophin-like cytokine, and ciliary neurotrophic factor (CNTF). Each cytokine binds a unique receptor, but each receptor binds a transmembrane protein called gp130. Mechanisms of signaling by gp130 involve interactions with tyrosine kinases of the JAK/TYK types and transcription factors in the STAT family. This mechanism is similar to those employed by the growth hormone receptor. 14.34 Diverse receptors recruit protein tyrosine kinases to the plasma membrane 635
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