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1 Chapter 26 Tyrosine Phosphorylation Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
2 FIGURE 26-1: Phosphotyrosine staining of a hippocampal neuron. A cultured rat hippocampal pyramidal neuron is stained with an antiphosphotyrosine antibody and detected by a secondary antibody conjugated to rhodamine. The staining reflects the presence of tyrosine-phosphorylated proteins throughout the neuron, including the cell body and synaptic regions. Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
3 FIGURE 26-2: Tyrosine phosphorylation and dephosphorylation. Protein tyrosine kinases (PTK) catalyze the transfer of the γ- phosphate group from ATP to the hydroxyl group of tyrosine residues, whereas protein tyrosine phosphatases (PTP) remove the phosphate group from phosphotyrosine. R represents the protein. Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
4 FIGURE 26-3: Schematic structures of receptor protein tyrosine kinase (RPTK) families. RPTKs can be divided into different families according to the structural features in the extracellular domain. Following the extracellular domain are the transmembrane and intracellular domains; the latter contains the catalytic domain. (Adapted from Blume-Jensen & Hunter, 2001 with permission.) Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
5 FIGURE 26-4: Nonreceptor protein tyrosine kinase (NRPTK) families. The family members are shown to the right and family name to the left of each NRPTK. Inset indicates the PTK catalytic domain and other domains for the regulation of localization and function. Kinases listed in bold have been associated with malignancies in humans and/or animal models. (Adapted from Blume-Jensen & Hunter, 2001 with permission.) Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
6 TABLE 26-1: Specificity and Affinity of SH2, Phosphotyrosine Binding (PTB) and SH3 Domains Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
7 FIGURE 26-5: SH2, SH3 and phosphotyrosine binding (PTB) domain-containing signaling proteins. SH2, SH3 and PTB domains are important molecular adhesives. These domains are found in enzymes and play important roles in the regulation of enzyme function. They also are found in proteins lacking any apparent catalytic domain, in which case they may serve as adaptor proteins, assembling signal-transduction complexes. The PTB domain of insulin receptor substrate-1 (IRS-1) shares a low degree of homology with the one on SHC. The black circle indicates a myristic acid moiety. PLC, phospholipase C; PI3-kinase, phosphatidylinositol-3-kinase; PTP, protein tyrosine phosphatase; PH, pleckstrin homology; SHP, SH2-containing PTP; Grb, growth-factor-receptor-binding protein. Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
8 FIGURE 26-6: (A) Crystal structure of the Src family kinase Hck. The catalytic domain of Src family tyrosine kinases consists of an N-terminal ATP-binding lobe and a C-terminal substrate-binding lobe. There is considerable flexibility in the relative orientation of these two lobes. The active conformation allows the proper alignment of the ATP terminal phosphate, the substrate and a catalytic glutamate residue (Glu310). However, the two lobes of an inactive kinase are swung apart, disrupting proper alignment. (With permission from Sicheri et al. (1997)) (B) Regulation of Src activity. Src activity can be regulated in a number of ways. In the inactive state, phosphorylated Y527 interacts with the SH2 domain. In addition, the SH3 domain binds the linker region between the SH1 and SH2 domains. These two intramolecular interactions pull the two lobes of the catalytic domain apart and inactivate the kinase. Therefore, dephosphorylation of Y527 by protein tyrosine phosphatases, e.g. CD45 and SHP-2, activates the kinase. Phosphorylation of Y527 by Csk inactivates the kinase. Inactivation is also achieved by dephosphorylating the autophosphorylation site Y416 by SHP-1. Alternatively, Src can be activated by binding to an autophosphorylated receptor protein tyrosine kinase (RPTK), such as the platelet-derived growth factor receptor. The RPTK autophosphorylation site binds to the Src SH2 domain and thus disrupts the inhibitory intramolecular interactions and activates the kinase. Association of Src with tyrosine-phosphorylated Fak activates the kinase in a similar fashion. Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
9 FIGURE 26-7: Activation of receptor protein tyrosine kinase (RPTK) by dimerization and transphosphorylation. Autophosphorylation is a key step in the activation of PTKs. To achieve autophosphorylation, some PTKs dimerize and transphosphorylate each other. Ligand binding induces dimerization of RPTKs so that the catalytic domains are in proximity for transphosphorylation. The autophosphorylated RPTK, thus, is activated. Some nonreceptor protein tyrosine kinases (NRPTKs) can be activated without dimerization (see Fig. 26-5 B). However, others, such as Jak/Tyk kinases, are activated by transphosphorylation. Jak/Tyk tyrosine kinases are associated constitutively with transmembrane proteins gp130 and leukemia-inhibitory factor receptor (LIFR)β. Extracellular ciliary neurotrophic factor (CNTF) induces the formation of a quaternary complex consisting of CNTF, LIFRβ, gp130 and another membrane protein known as CNTF receptor α. Consequently, the associated Jak/Tyk are dimerized, allowing transphosphorylation and activation. Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
10 FIGURE 26-8: Recruitment of different signaling molecules to different tyrosine-phosphorylation sites on receptor protein tyrosine kinases (RPTKs). RPTKs usually are autophosphorylated on several different sites. Each tyrosine-phosphorylation site has a unique sequence for interaction with specific signaling molecules containing SH2 or phosphotyrosine-binding (PTB) domains. This provides specificity and diversity for RPTK signaling. PDGFR, platelet-derived growth factor receptor; EGFR, epidermal growth factor receptor; PLC, phospholipase C; GAP, GTPase-activating protein; Grb2, growth factor receptor binding protein; PI3K, phosphatidylinositol-3-kinase; SHC, SH2-containing protein; SHP, SH2-domain containing tyrosine phosphatase. Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
11 Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved. FIGURE 26-9: Major signal-transduction mechanisms in TrkB/BDNF-mediated neuronal survival and differentiation. (A) BDNF binds to TrkB and induces autophosphorylation on three different sites in the intracellular domain. One site interacts with SHC, which eventually leads to the activation of mitogen-activated protein kinase (MAPK) and transcription. TrkB also induces tyrosine phosphorylation of suc-associated neurotrophic factor-induced target (SNT) via a mechanism independent of all known signaling mechanisms. MAPK-induced transcription and SNT tyrosine phosphorylation are believed to be important in neuronal differentiation. TrkB autophosphorylation also activates phosphatidylinositol-3-kinase (PI3K) by recruiting it to the membrane. PI3K generates PI-3,4,5-trisphosphate from PI-4,5- bisphosphate. PI-3,4,5-trisphosphate is hydrolyzed to yield PI-3,4-bisphosphate, which activates Akt by translocating it to the membrane. Activated Akt can promote neuronal survival. Grb2, growth factor receptor binding protein, promotes survival and growth of neurons and other cells through Ras or GRB-associated binder 1 (GAB1). Phosphorylation at Y816 recruits and activates phospholipase C 1 (PLC 1), resulting in production of inositol-1,4,5-trisphosphate (Ins(1,4,5)P 3 ) and diacylglycerol (DAG). Whereas DAG stimulates protein kinase C (PKC) isoforms, (Ins(1,4,5)P 3 ) promotes the release of Ca 2+ from internal stores and subsequent activation of Ca 2+ /calmodulin (Ca 2+ /CaM)-dependent protein kinases (CaMKII, CaMKK and CaMKIV). These pathways can be functionally separated, so mutation at Y816 affects the PLC 1 pathway, but not Ras/MAPK or PI3K pathways that are regulated by SHC. BDNF, brain-derived neurotrophic factor; FRS2, fibroblast growth factor receptor substrate 2; GRB2, growth factor receptor-bound protein 2; PDPK1, 3-phosphoinositide-dependent protein kinase 1; PtdIns(4,5) P 2, phosphatidylinositol- 4,5-bisphosphate; RSK, ribosomal protein S6 kinase; SHP2, SRC-homology phosphatase 2; SOS, son of sevenless.
12 Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved. FIGURE 26-9: (Continued) (B) TrkB signaling affects both pre- and postsynaptic function. On the presynaptic side, BDNF binding activates Src-family NRPTK, which triggers endocytosis of TrkB/BDNF complex for return to the neuronal cell body by a retrograde transport of a signaling endosome (see Fig. 7-7). In addition, BDNF can increase Ca 2+ influx through transient receptor potential (TRPC) channels and enhance neurotransmitter release. On the postsynaptic side, there are functional interactions between TrkB signaling and glutamate receptors as well as TRP channels. NMDAR function is enhanced by activation of the Src family NRPTK, Fyn, which is activated by BDNF binding to TrkB. Fyn mediated phosphorylation of NMDARs increases the open probability of the NMDAR ion channel. Concurrently, BDNF binding to TrkB can activate PLC, which leads to Ins(1,4,5)P 3 -dependent Ca 2+ store depletion, which activates influx of Ca2 2+ and Na + through TRPC3 as well as altering the expression and trafficking of AMPARs. Ca 2+ influx through NMDARs activates α-Ca 2+ /calmodulin-dependent protein kinase II (αCaMKII) and contributes to the long-term potentiation through positive regulation of NMDARs and AMPARs. Activation of postsynaptic signaling pathways leads to increased release of BDNF from the postsynaptic cell, leading to increased synaptic strength and promoting survival of the presynaptic neuron through retrograde signaling.DAG, diacylglycerol; PtdIns(4,5)P2, phosphatidylinositol-4,5-bisphosphate. Adapted from L. Minichiello, 850 (2009) figures 1 and 2.
13 Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved. FIGURE 26-10: Schematic structures of nonreceptor protein tyrosine phosphatases (NRPTPs) and receptor protein tyrosine phosphatases (RPTPs). NRPTPs contain a catalytic domain and various regulatory domains. RPTPs are composed of an extracellular domain, a transmembrane domain and an intracellular domain with one or two catalytic domains. However, due to alternative splicing of some PTP genes, a single gene can produce both RPTP and NRPTP products from the same gene. Like RPTKs, the structural features of the extra-cellular domains divide the RPTPs into different families. For both RPTPs and NRPTPs, the non-catalytic domains contain motifs that serve a structural or regulatory function as well as help to define various subfamilies based on sequence similarity. Individual PTPs are designated by a name that is commonly used in the literature. Where necessary, the gene symbol is given in parentheses. (Adapted from Tonks. (2006))
14 Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved. FIGURE 26-11: Schematic structures of Dual Specificity Kinases, which have features of both PTP and Serine/Threonine Phosphatases. They are classified as PTPs due to the presence of the signature motif HC(X)5R in the active site, but the catalytic domain is smaller that classical PTPs and they are more heterogeneous in structure. The non-catalytic domains contain motifs that serve a structural or regulatory function. These non-catalytic domains define various subfamilies based on sequence similarity, with individual DSPs designated by a name that is commonly used in the literature. Where necessary, the gene symbol is given in parentheses. Although the DSPs are related to PTPs and many have PTP activity, some remove phosphate from other moieties, such as RNA () and lipids (MTM, myotubularins). (Adapted with permission from (Tonks, 2006))
15 Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved. FIGURE 26-12: Examples of the role of protein tyrosine kinases and protein tyrosine phosphatases in the lifetime of a neuron. (N). Tyrosine phosphorylation appears to be an important signal-transduction mechanism in every step in the development of a neuron, starting from the survival and differentiation of stem cells, to axon guidance and synaptogenesis and to synaptic transmission at a mature synapse. Examples of each step are given on the right, indicating the receptors and their ligands. Eph, erythropoietin-producing hepatocellular factor; RAGS, repulsive axon guidance signal, MuSK, muscle-specific kinase; ARIA, acetylcholine-receptor-inducing activity.
16 Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved. FIGURE 26-13: Transmembrane topology of three ligand-gated ion channel subunits and their potential domains for tyrosine phosphorylation. Both the acetylcholine receptor (AchR) and GABA A receptor (GABA A R) subunits have four transmembrane domains with both the N- and C-termini on the outside. Tyrosine phosphorylation sites are present within the large intracellular loop between the third and fourth transmembrane domains. N-methyl-D-aspartate (NMDA) receptor subunits have a somewhat different topology. They have three transmembrane domains and a membrane-spanning domain. The delayed rectifier potassium channel (RAK) has six transmembrane domains and a membrane-spanning domain. Mutagenesis studies have revealed the intracellular N-terminus as the tyrosine-phosphorylation site-bearing region, although other studies have suggested the presence of other tyrosine-phosphorylation sites.
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