Principles of cell signaling - UT Southwestern

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39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 632 Generic G Protein small or heterotrimer MAP4K MAP3K MAP2K MAPK Major targets: Transcription factor Protein kinase Output S. cerevisiae Gβγ Ste20p Ste11p Ste7p Fus3p Ste12p Mating MAPK pathways Mammals Ras Rac/Cdc42 Rac ? Ste20 Ste20 PAK/PKC ? family family Raf MEK1 MEK2 ERK1 ERK2 Elk-1 Rsk many MEK4 MEK7 JNK1 JNK2 JNK3 c-Jun ATF2 many MEK3 MEK6 p38α p38β p38γ p38δ MEF2 MAPKAPK2 Proliferation Development Differentiation (and other processes) MEKK2 MEKK3 MEK5 ERK5 MEF2 FIGURE 14.38 MAPK pathways can be regulated by a diverse group of upstream regulatory mechanisms that often include adaptors, small G proteins, and MAP4Ks. These molecules impinge on the activities of MAP3Ks. MAP3Ks regulate one or more MAP2Ks depending on localization and scaffolding. The MAP2Ks display great selectivity for a single MAPK type. MAPKs have overlapping and unique substrates and participate in signaling cascades leading to many cellular responses. Rsk Tyr and a Thr residue creates cooperative activation of the MAPK; this is another mechanism, in addition to those described for PKA and calmodulin, to introduce a threshold and apparently cooperative behavior into the pathway over a narrow range of input signal. This multistep cascade provides multiple sites for modulatory inputs from other pathways. Stabilized interactions between components are also important. MAP2Ks, as well as MAPK substrates and MAPK phosphatases, generally contain a basic/hydrophobic docking motif that interacts with acidic residues and binds in a hydrophobic groove on the MAPK catalytic domain. Additional components including scaffolds are necessary for the efficient activation of MAPK cascades in cells and usually have additional functions. Several scaffolds have been identified that bind to two or more components for each of the three major MAPK cascades, the ERK1/2, JNK1-3, and p38 α, β, γ, and δ cascades. The ERK1/2 pathway is regulated by most cell surface receptors, including receptors that employ tyrosine kinases, GPCRs, and others. The PDGF receptor, like most receptor systems, activates the ERK1/2 cascade through Ras. PDGF stimulates autophosphorylation of its receptor and the subsequent association of effectors with its cytoplasmic domain (see 14.30 Diverse signaling mechanisms are regulated by protein tyrosine kinases). In response to PDGF, ERK1/2 promotes cell proliferation and differentiation by phosphorylation of membrane enzymes, proteins involved in determining cell shape and motility, and also by concentrating in the nucleus to phosphorylate regulatory factors that control transcription. 14.33 Cyclin-dependent protein kinases control the cell cycle Key concepts • The cell cycle is regulated by cyclin-dependent protein kinases (CDKs). • Activation of CDKs involves protein binding, dephosphorylation, and phosphorylation. Cell division is regulated positively and negatively by factors that stimulate proliferation and inputs that monitor cell state. The sum of these factors is integrated in the regulation of cyclindependent protein kinases (CDKs). CDKs are protein serine/threonine kinases that are major regulators of cell cycle progression. Most CDKs are regulated both by kinases and phosphatases and by association with other proteins called cyclins. Cyclins are synthesized and degraded every cell cycle. Because most CDKs are dependent upon cyclin binding for activation, the timing of the synthesis and degradation of individual cyclins determines when a CDK will function. The most notable noncycling member of the CDK family is Cdk5, which is highly expressed in terminally differentiated neurons. Cdk5 binds the non-cyclin protein p35 as its activating subunit. We will briefly examine the regulation of Cdc2, a major CDK in both mammals and yeast. The first step in regulation of Cdc2 is the association with cyclin. A second step required for activation of Cdc2 is phosphorylation of a Thr 632 CHAPTER 14 Principles of cell signaling
39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 633 CDKs require cyclin binding for activation Tyr15 Lys33 Glu51 Cdk2 Cyclin A FIGURE 14.39 The view of the crystal structure of CDK2 bound to cyclin A shows residues in the ATP binding site. The enlargement on the right shows the interaction between Lys33 and Glu51, catalytic residues that interact with ATP to promote phosphoryl transfer. Tyr15 is phosphorylated in inactive forms of CDK2. A phosphoryl group on Tyr15 inhibits CDK activity by interfering with ATP binding. Structure generated from Protein Data Bank file 1JST. residue in its activation loop by another CDK type kinase. In spite of its association with cyclin, this form of Cdc2 is not yet active due to inhibitory phosphorylation of Tyr and Thr residues in the ATP binding pocket. Release of inhibition by dephosphorylation of the residues in the ATP pocket is catalyzed by the Cdc25 family of phosphoprotein phosphatases, resulting in activation of Cdc2. The proximity of the Tyr residue to catalytic residues is shown in FIGURE 14.39. The complexity of activation of CDKs makes possible the imposition of cell cycle checkpoints. For more on CDKs and cyclins see 11.4 The cell cycle is a cycle of CDK function. 14.34 Diverse receptors recruit protein tyrosine kinases to the plasma membrane Key concepts • Receptors that bind protein tyrosine kinases use combinations of effectors similar to those used by receptor tyrosine kinases. • These receptors often bind directly to transcription factors. Many receptors act through protein tyrosine kinases, but their cell surface receptors lack kinase activity. Instead, these receptors act by recruiting and activating protein tyrosine kinases at the plasma membrane. In this group of receptors are integrins, which are key molecules involved in cell adhesion, growth hormone receptors, and receptors that mediate inflammatory and immune responses. While their structures vary enormously, their mechanisms of action are related. Integrins are receptors whose major function is to attach cells to the extracellular matrix. They also mediate some interactions with proteins on other cells, as depicted in FIGURE 14.40. Ligands for integrins include a number of extracellular matrix proteins, such as fibronectin, as well as cell surface proteins that cooperate in cell-cell interactions. Integrin ligation provides cells with information about their environment that influences cell behavior. Ligation of integrins initiates signals that control cell programs, including cell cycle entry, proliferation, survival, differentiation, changes in cell shape, and motility, as well as fine-tuning responses to other ligands. For more details on integrins see 15.13 Most integrins are receptors for extracellular matrix proteins and 15.14 Integrin receptors participate in cell signaling. 14.34 Diverse receptors recruit protein tyrosine kinases to the plasma membrane 633
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Principles of cell signaling - UT Southwestern

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