DOCSLIB.ORG

G Protein Regulation of MAPK Networks

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
G Protein Regulation of MAPK Networks Oncogene (2007) 26, 3122–3142 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW G Protein regulation of MAPK networks ZG Goldsmith and DN Dhanasekaran Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA G proteins provide signal-coupling mechanisms to hepta- the a-subunits has been used as a basis for the helical cell surface receptors and are criticallyinvolved classification of G proteins into Gs,Gi,Gq and G12 in the regulation of different mitogen-activated protein families in which the a-subunits that show more than kinase (MAPK) networks. The four classes of G proteins, 50% homology are grouped together (Simon et al., defined bythe G s,Gi,Gq and G12 families, regulate 1991). In G-protein-coupled receptor (GPCR)-mediated ERK1/2, JNK, p38MAPK, ERK5 and ERK6 modules by signaling pathways, ligand-activated receptors catalyse different mechanisms. The a- as well as bc-subunits are the exchange of the bound GDP to GTP in the a-subunit involved in the regulation of these MAPK modules in a following which the GTP-bound a-subunit disassociate context-specific manner. While the a- and bc-subunits from the receptor as well as the bg-subunit. The GTP- primarilyregulate the MAPK pathwaysvia their respec- bound a-subunit and the bg-subunit stimulate distinct tive effector-mediated signaling pathways, recent studies downstream effectors including enzymes, ion channels have unraveled several novel signaling intermediates and small GTPase, thus regulating multiple signaling including receptor tyrosine kinases and small GTPases pathways including those involved in the activation of through which these G-protein subunits positivelyas well mitogen-activated protein kinase (MAPK) modules as negativelyregulate specific MAPK modules. Multiple (Johnson and Dhanasekaran, 1989; Hepler and Gilman, mechanisms together with specific scaffold proteins that 1992; Dhanasekaran et al., 1995; Dhanasekaran and can link G-protein-coupled receptors or G proteins to Prasad, 1998; Rozengurt, 1998). distinct MAPK modules contribute to the context-specific MAPK modules regulate many critical signaling and spatio-temporal regulation of mitogen-activated pathways including cell proliferation, differentiation protein signaling networks byG proteins. and apoptosis (Fanger et al., 1997; Minden and Karin, Oncogene (2007) 26, 3122–3142. doi:10.1038/sj.onc.1210407 1997; Dhanasekaran and Premkumar Reddy, 1998; Gutkind, 1998; Garrington and Johnson, 1999; Davis, Keywords: GPCR; signal transduction; G protein; 2000; Chang and Karin, 2001). Each of these modules MAPK; oncogene; cancer consists of at least three distinct kinases, namely an upstream mitogen-activated protein (MAP) kinase kinase kinase (MAP3K), a MAP kinase kinase (MAP2K) and a downstream MAP kinase (MAPK). In a typical signaling pathway, growth factor stimulated Introduction small GTPases such as Ras, CDC42, and Rac activate an upstream MAP kinase kinase kinase kinase Heterotrimericguanine nucleotide-binding proteins, (MAP4K), following which the MAP kinase cascades or G proteins, consisting of a-, b-andg-subunits, proceed through the sequential phosphorylation of transduce signals from heptahelical cell surface receptors constituent MAP3K, MAP2K and MAPK (Minden to intracellular effectors (Simon et al., 1991; Hepler and Karin, 1997; Dhanasekaran and Premkumar and Gilman, 1992; Conklin and Bourne, 1993). The Reddy, 1998; Davis, 2000; Chang and Karin, 2001). a-subunit is a 37–42 kDa protein, which contains Activated MAP kinases translocate from the cytosol to the guanine nucleotide-binding pocket along with the the nucleus where they regulate the activities of various intrinsicGTPase activity.The 35-kDa b-subunit and the transcription factors through phosphorylation (Khokh- 8–11-kDa g-subunit are tightly associated with each latchev et al., 1998; Brunet et al., 1999). GPCRs, other and are often referred to as a single entity, the primarily through their cognate G proteins, regulate bg-subunit (Simon et al., 1991; Hepler and Gilman, these three-tier MAPK phospho-relay systems to 1992; Conklin and Bourne, 1993). To date, 17 different modulate the expression of specific primary as well as a-subunits, five b-subunits and 12 g-subunits have secondary response genes involved in cell proliferation, been identified. However, the amino acid identity of differentiation and apoptosis (Gutkind, 2000; Kranen- burg and Moolenaar, 2001; Werry et al., 2005). G proteins have been shown to regulate diverse transcrip- Correspondence: Dr DN Dhanasekaran, Fels Institute for Cancer Research and Molecular Biology, Temple University School of tion factors such as AP-1 (Araki et al., 1997), NF-kB, Medicine, Philadelphia, PA 19140, USA. CRE, SRE (Takeuchi and Fukunaga, 2003), ATF1 E-mail: [email protected] (Ghosh et al., 2002), STAT3 (Sellers et al., 1999), ELK1 G Proteins and MAPKs ZG Goldsmith and DN Dhanasekaran 3123 (Todisco et al., 1997), Egr-1 (Gerasimovskaya et al., studies focused on defining the oncogenic pathways 2002), HIF-1a (Sodhi et al., 2000), MEF2 (Fukuhara regulated by the gsp oncogene that encodes the et al., 2000a, b) via ERK-, JNK-, p38MAPKs- or ERK5 constitutively activated mutants of Gas (Landis et al., modules. However, only recently the dynamic and 1989; Lyons et al., 1990). Functional characterization of multilayered mechanisms by which G proteins regulate these activating mutations indicated that the ectopic these MAPK networks have begun to be unraveled. This expression of Gas could stimulate ERK1/2 in different review is focused on analysing the mechanisms by which cell types (Faure et al., 1994). Using mutant S49 G proteins regulate different MAPK networks in a lymphoma cell lines that lack Gas or PKA, it was context-specific manner. further established that Gas and PKA are required to couple b2-AR signaling to ERK1/2 module (Wan and Huang, 1998). Analysis of such Gas-mediated stimula- tion of ERK1/2 indicated that it was mediated by a Regulation of MAPKs byG s pathway involving Rap-1 and its activation of B-Raf, one of the isoforms of Raf (Vossler et al., 1997; Wan G , defined by the a-subunit Ga , transduces signals s s and Huang, 1998; Schmitt and Stork, 2000; Weissman from G -coupled heptahelical receptors to adenylyl s et al., 2002; Dumaz and Marais, 2005; Houslay, 2006; cyclase that converts ATP to cAMP and subsequently Wang et al., 2006b). One of the mechanisms through to cAMP-mediated activation of protein kinase A which Ga activates Rap-1 involves cAMP-mediated (PKA) (Gilman, 1987; Hepler and Gilman, 1992). s direct activation of EPAC (exchange protein directly Consequently, as depicted in Figure 1, cAMP as well activated by cAMP), a guanine nucleotide exchange as cAMP-activated PKA have been shown to play a factor (GEF) specific for Rap-1 (de Rooij et al., 1998; major role in Ga -mediated stimulation as well as inhi- s Quilliam et al., 2002; Bos, 2006). In rat kidney cortical bition of MAPK modules such as those of ERK1/2, collecting duct cells, it has been shown that the ERK5 and p38MAPK (Cook and McCormick, 1993; stimulation of Ga and subsequent generation of cAMP Graves et al., 1993; Wu et al., 1993; Wan and s leads to the activation of EPAC, which stimulates Huang, 1998; Zheng et al., 2000; Laroche-Joubert GDP–GTP exchange in Rap-1. The GTP-bound Rap-1, et al., 2002; Stork and Schmitt, 2002; Dumaz and thus stimulated, activates B-Raf and the downstream Marais, 2005; Houslay, 2006; Pearson et al., 2006). ERK1/2 modules (Laroche-Joubert et al., 2002). The observation that the introduction of antibodies to Epac-1, Gas stimulation of ERK1/2 Rap-1 and B-Raf into these cells inhibited Gs-mediated The initial evidence that Gas is involved in the activation of ERK1/2 module established the linear regulation of ERK1/2 signaling module consisting pathway leading from cAMP to the activation of of a MAP3K–MAP2K–MAPK module defined by ERK1/2 module involving Epac-1, Rap-1 and B-Raf Raf, MEK1/2 and ERK1/2, respectively, came from (Laroche-Joubert et al., 2002). Adenylyl Cylclase P s P cAMP Ras EPAC PKA Src C-Raf C3G MEK-1/2 ERK-1/2 Rap1 MEKK2/3 MAP3K MEK5 MKK3/6 ERK5 B-Raf p38MAPK MEK-1/2 ERK-1/2 Figure 1 Gs regulation of ERK1/2. Gas stimulates the B-Raf-mediated activation of ERKs via Rap-1 or Ras and inhibits C-Raf- mediated activation of ERKs by phosphorylating C-Raf through PKA. Gas has also been shown to stimulate p38MAPK and inhibit ERK-5 modules via PKA-dependent mechanism. The dashed lines indicate the pathways that have not been fully resolved. Oncogene G Proteins and MAPKs ZG Goldsmith and DN Dhanasekaran 3124 Although further studies confirmed the role of Rap-1 ERK pathway involves PKA-mediated phosphorylation in Gas-stimulated activation of ERK1/2 module, they of a specific isoform of Raf, known as Raf-1 or C-Raf also indicated that Gas stimulation of ERK1/2 module (Wu et al., 1993; Dhillon et al., 2002). C-Raf contains via Rap-1 involves a Rap-1 GEF other than EPAC in three PKA-target Serines, namely Ser 43, 259 and 621 many cell types (Stork and Schmitt, 2002). The cAMP (Morrison et al., 1993), all of which can be phosphory- analog, 8-(4-chloro-phenylthio)-20-O-methyladenosine- lated in vitro by PKA (Wu et al., 1993; Hafner et al., 30,50-cyclic monophosphate (8CPT-2Me-cAMP) that 1994; Mischak et al., 1996). Mutational analyses of can activate EPAC, but not PKA, proved useful in C-Raf indicated that the Gas-mediated cAMP–PKA identifying the alternate pathway through which Gas signaling axis inhibits C-Raf through the phosphoryla- activated ERK1/2 via Rap-1 (Enserink et al., 2002). The tion of Ser-259 (Dhillon et al., 2002). The PKA observations that 8CPT-2Me-cAMP stimulated EPAC phosphorylation of Ser-259 of C-Raf attenuates the but failed to activate Rap-1-dependent activation of phosphorylation of Ser-338, which is involved in the ERK suggested that EPAC might not be involved in activation of C-Raf (Dhillon et al., 2002), thus providing Rap-1-mediated activation of ERK1/2 module in all a molecular basis for Gas-mediated inhibition of C-Raf– the cells (Enserink et al., 2002).
Load more

Recommended publications
  • Dynamin Functions and Ligands: Classical Mechanisms Behind
    1521-0111/91/2/123–134$25.00 http://dx.doi.org/10.1124/mol.116.105064 MOLECULAR PHARMACOLOGY Mol Pharmacol 91:123–134, February 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics MINIREVIEW Dynamin Functions and Ligands: Classical Mechanisms Behind Mahaveer Singh, Hemant R. Jadhav, and Tanya Bhatt Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Pilani Campus, Rajasthan, India Received May 5, 2016; accepted November 17, 2016 Downloaded from ABSTRACT Dynamin is a GTPase that plays a vital role in clathrin-dependent pathophysiology of various disorders, such as Alzheimer’s disease, endocytosis and other vesicular trafficking processes by acting Parkinson’s disease, Huntington’s disease, Charcot-Marie-Tooth as a pair of molecular scissors for newly formed vesicles originating disease, heart failure, schizophrenia, epilepsy, cancer, dominant ’ from the plasma membrane. Dynamins and related proteins are optic atrophy, osteoporosis, and Down s syndrome. This review is molpharm.aspetjournals.org important components for the cleavage of clathrin-coated vesicles, an attempt to illustrate the dynamin-related mechanisms involved phagosomes, and mitochondria. These proteins help in organelle in the above-mentioned disorders and to help medicinal chemists division, viral resistance, and mitochondrial fusion/fission. Dys- to design novel dynamin ligands, which could be useful in the function and mutations in dynamin have been implicated in the treatment of dynamin-related disorders. Introduction GTP hydrolysis–dependent conformational change of GTPase dynamin assists in membrane fission, leading to the generation Dynamins were originally discovered in the brain and identi- of endocytic vesicles (Praefcke and McMahon, 2004; Ferguson at ASPET Journals on September 23, 2021 fied as microtubule binding partners.
    [Show full text]
  • Active Rac1 Detection Kit 2012 09/20
    Active Rac1 Detection Kit 1 Kit Orders n 877-616-CELL (2355) (30 immunoprecipitations) [email protected] Support n 877-678-TECH (8324) [email protected] Web n www.cellsignal.com rev. 09/24/20 #8815 For Research Use Only. Not For Use In Diagnostic Procedures. Species Cross-Reactivity: H, M Components Ship As: 11894S Item # Kit Quantity Storage Temp Description: The Active Rac1 Detection Kit provides all GTPgS 11521 1 X 50 µl –80°C reagents necessary for measuring activation of Rac1 GTPase in the cell. GST-PAK1-PBD fusion protein is used to bind GDP 11522 1 X 50 µl –80°C the activated form of GTP-bound Rac1, which can then be Components Ship As: 11894S Item # Kit Quantity Storage Temp immunoprecipitated with glutathione resin. Rac1 activation levels are then determined by western blot using a Rac1 GST-Human PAK1-PBD 8659 1 X 600 µg –20°C Mouse mAb. Rac1 Mouse mAb 8631 1 X 50 µl –20°C Specificity/Sensitivity: Active Rac1 Detection Kit detects Components Ship As: 11860S Item # Kit Quantity Storage Temp endogenous levels of GTP-bound (active) Rac1 as shown in Lysis/Binding/Wash Buffer 11524 1 X 100 mL 4°C Figure 1. This kit detects proteins from the indicated species, as determined through in-house testing, but may also detect Glutathione Resin 11523 1 X 3 ml 4°C homologous proteins from other species. SDS Sample Buffer 11525 1 X 1.5 ml 4°C Background: The Ras superfamily of small GTP-binding Spin Cup and Collection Tubes 11526 1 X 30 vial RT proteins (G proteins) comprise a large class of proteins (over 150 members) that can be classified into at least five families based on their sequence and functional similarities: 1 2 3 4 Figure 1.
    [Show full text]
  • Rac1 Accumulates in the Nucleus During the G2 Phase of the Cell
    Published Online: 28 April, 2008 | Supp Info: http://doi.org/10.1083/jcb.200801047 JCB: ARTICLE Downloaded from jcb.rupress.org on May 9, 2018 Rac1 accumulates in the nucleus during the G2 phase of the cell cycle and promotes cell division David Michaelson , 2,5 Wasif Abidi , 2,5 Daniele Guardavaccaro , 4,5 Mo Zhou, 3,5 Ian Ahearn , 3,5 Michele Pagano , 4,5 and Mark R. Philips 1,2,3,5 1 Department of Medicine, 2 Department of Cell Biology, 3 Department of Pharmacology, 4 Department of Pathology, and the 5 New York University Cancer Institute, New York University School of Medicine, New York, NY 10016 ac1 regulates a wide variety of cellular processes. zation of cells stably expressing low levels of GFP-Rac1, The polybasic region of the Rac1 C terminus func- and time-lapse microscopy of asynchronous cells revealed Rtions both as a plasma membrane – targeting motif Rac1 accumulation in the nucleus in late G2 and exclu- and a nuclear localization sequence (NLS). We show that sion in early G1. Although constitutively active Rac1 re- a triproline N-terminal to the polybasic region contributes stricted to the cytoplasm inhibited cell division, activated to the NLS, which is cryptic in the sense that it is strongly Rac1 expressed constitutively in the nucleus increased the inhibited by geranylgeranylation of the adjacent cysteine. mitotic rate. These results show that Rac1 cycles in and out Subcellular fractionation demonstrated endogenous Rac1 of the nucleus during the cell cycle and thereby plays a in the nucleus and Triton X-114 partition revealed that this role in promoting cell division.
    [Show full text]
  • Crystal Structure of a Small G Protein in Complex with the Gtpase
    letters to nature of apolipoproteins2,12–14. However, our results show that the residues lipoprotein metabolism involving cell surface heparan sulfate proteoglycans. J. Biol. Chem. 269, 2764– 2+ 2772 (1994). in the conserved acidic motif of LR5 are buried to participate in Ca 16. Innerarity, T. L., Pitas, R. E. & Mahley, R. W. Binding of arginine-rich (E) apoprotein after coordination, instead of being exposed on the surface of the domain recombination with phospholipid vesicles to the low density lipoprotein receptors of fibroblasts. J. Biol. Chem. 254, 4186–4190 (1979). (Fig. 4a). Although lipoprotein uptake by members of the LDLR 17. Otwinowski, Z. & Minor, W. Data Collection and Processing (eds Sawyer, L., Isaacs, N. & Bailey, S.) family may involve an electrostatic component, perhaps through 556–562 (SERC Daresbury Laboratory, Warrington, UK, 1993). association of the lipoproteins with cell-surface proteoglycans15, the 18. CCP4. The SERC (UK) Collaborative Computing Project No. 4 A Suite of Programs for Protein Crystallography (SERC Daresbury Laboratory, Warrington, UK, 1979). LR5 structure demonstrates that the primary role for the conserved 19. Cowtan, K. D. Joint CCP4 and ESF-EACBM Newsletter on Protein Crystallography 31, 34–38 (1994). acidic residues in LDL-A modules is structural. It has been noted 20. Jones, T. A., Zou, J. Y., Cowan, S. W. & Kjeldgaard, M. Improved methods for binding protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 previously that only lipid-associated apolipoproteins bind with (1991). 16 high affinity to the LDLR ; the LR5 structure suggests an alternative 21.
    [Show full text]
  • Ras Gtpase Chemi ELISA Kit Catalog No
    Ras GTPase Chemi ELISA Kit Catalog No. 52097 (Version B3) Active Motif North America 1914 Palomar Oaks Way, Suite 150 Carlsbad, California 92008, USA Toll free: 877 222 9543 Telephone: 760 431 1263 Fax: 760 431 1351 Active Motif Europe Waterloo Atrium Drève Richelle 167 – boîte 4 BE-1410 Waterloo, Belgium UK Free Phone: 0800 169 31 47 France Free Phone: 0800 90 99 79 Germany Free Phone: 0800 181 99 10 Telephone: +32 (0)2 653 0001 Fax: +32 (0)2 653 0050 Active Motif Japan Azuma Bldg, 7th Floor 2-21 Ageba-Cho, Shinjuku-Ku Tokyo, 162-0824, Japan Telephone: +81 3 5225 3638 Fax: +81 3 5261 8733 Active Motif China 787 Kangqiao Road Building 10, Suite 202, Pudong District Shanghai, 201315, China Telephone: (86)-21-20926090 Hotline: 400-018-8123 Copyright 2021 Active Motif, Inc. www.activemotif.com Information in this manual is subject to change without notice and does not constitute a commit- ment on the part of Active Motif, Inc. It is supplied on an “as is” basis without any warranty of any kind, either explicit or implied. Information may be changed or updated in this manual at any time. This documentation may not be copied, transferred, reproduced, disclosed, or duplicated, in whole or in part, without the prior written consent of Active Motif, Inc. This documentation is proprietary information and protected by the copyright laws of the United States and interna- tional treaties. The manufacturer of this documentation is Active Motif, Inc. © 2021 Active Motif, Inc., 1914 Palomar Oaks Way, Suite 150; Carlsbad, CA 92008.
    [Show full text]
  • Calmodulin-Dependent Protein Kinase II–Protein Phosphatase 1 Switch Facilitates Specificity in Postsynaptic Calcium Signaling
    An ultrasensitive Ca2؉͞calmodulin-dependent protein kinase II–protein phosphatase 1 switch facilitates specificity in postsynaptic calcium signaling J. Michael Bradshaw*†‡, Yoshi Kubota*, Tobias Meyer†, and Howard Schulman* Departments of *Neurobiology and †Molecular Pharmacology, Stanford University School of Medicine, Stanford, CA 94305 Edited by Roger A. Nicoll, University of California, San Francisco, CA, and approved July 21, 2003 (received for review May 7, 2003) The strength of hippocampal synapses can be persistently in- hence would provide a distinct Ca2ϩ activation region for creased by signals that activate Ca2؉͞calmodulin-dependent pro- CaMKII compared with other Ca2ϩ-activated enzymes at the tein kinase II (CaMKII). This CaMKII-dependent long-term potenti- synapse. In fact, it has been hypothesized that the signaling ation is important for hippocampal learning and memory. In this network controlling CaMKII autophosphorylation is a bistable work we show that CaMKII exhibits an intriguing switch-like type of switch that allows CaMKII to remain autophosphory- activation that likely is important for changes in synaptic strength. lated long after Ca2ϩ returns to a basal level (16). We found that autophosphorylation of CaMKII by itself showed a In this work we demonstrate experimentally that CaMKII 2؉ Ϸ ϩ steep dependence on Ca concentration [Hill coefficient (nH) 5]. responds in a switch-like fashion to Ca2 : CaMKII transitions 2؉ Ϸ However, an even steeper Ca dependence (nH 8) was observed rapidly from little to near-total autophosphorylation over a when autophosphorylation is balanced by the dephosphorylation narrow range of Ca2ϩ. Interestingly, this switch-like response was activity of protein phosphatase 1 (PP1).
    [Show full text]
  • Plant Mitogen-Activated Protein Kinase Signaling Cascades Guillaume Tena*, Tsuneaki Asai†, Wan-Ling Chiu‡ and Jen Sheen§
    392 Plant mitogen-activated protein kinase signaling cascades Guillaume Tena*, Tsuneaki Asai†, Wan-Ling Chiu‡ and Jen Sheen§ Mitogen-activated protein kinase (MAPK) cascades have components that link sensors/receptors to target genes emerged as a universal signal transduction mechanism that and other cellular responses. connects diverse receptors/sensors to cellular and nuclear responses in eukaryotes. Recent studies in plants indicate that In the past few years, it has become apparent that mitogen- MAPK cascades are vital to fundamental physiological functions activated protein kinase (MAPK) cascades play some of the involved in hormonal responses, cell cycle regulation, abiotic most essential roles in plant signal transduction pathways stress signaling, and defense mechanisms. New findings have from cell division to cell death (Figure 1). MAPK cascades revealed the complexity and redundancy of the signaling are evolutionarily conserved signaling modules with essen- components, the antagonistic nature of distinct pathways, and tial regulatory functions in eukaryotes, including yeasts, the use of both positive and negative regulatory mechanisms. worms, flies, frogs, mammals and plants. The recent enthu- siasm for plant MAPK cascades is backed by numerous Addresses studies showing that plant MAPKs are activated by hor- Department of Molecular Biology, Massachusetts General Hospital, mones, abiotic stresses, pathogens and pathogen-derived Department of Genetics, Harvard Medical School, Wellman 11, elicitors, and are also activated at specific stages during the 50 Blossom Street, Boston, Massachusetts 02114, USA cell cycle [2]. Until recently, studies of MAPK cascades in *e-mail: [email protected] †e-mail: [email protected] plants were focused on cDNA cloning [3,4] and used a ‡e-mail: [email protected] MAPK in-gel assay, MAPK and tyrosine-phosphate anti- §e-mail: [email protected] bodies, and kinase inhibitors to connect signals to MAPKs Current Opinion in Plant Biology 2001, 4:392–400 [2].
    [Show full text]
  • (PDE 1 B 1) Correlates with Brain Regions Having Extensive Dopaminergic Innervation
    The Journal of Neuroscience, March 1994, 14(3): 1251-l 261 Expression of a Calmodulin-dependent Phosphodiesterase lsoform (PDE 1 B 1) Correlates with Brain Regions Having Extensive Dopaminergic Innervation Joseph W. Polli and Randall L. Kincaid Section on Immunology, Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland 20852 Cyclic nucleotide-dependent protein phosphorylation plays PDE implies an important physiological role for Ca2+-regu- a central role in neuronal signal transduction. Neurotrans- lated attenuation of CAMP-dependent signaling pathways mitter-elicited increases in cAMP/cGMP brought about by following dopaminergic stimulation. activation of adenylyl and guanylyl cyclases are downre- [Key words: CAMP, cyclase, striatum, dopamine, basal gulated by multiple phosphodiesterase (PDE) enzymes. In ganglia, DARPP-321 brain, the calmodulin (CaM)-dependent isozymes are the major degradative activities and represent a unique point of Cyclic nucleotides, acting as “second messengers”or via direct intersection between the cyclic nucleotide- and calcium effects, regulate a diverse array of neuronal functions, from ion (Ca*+)-mediated second messenger systems. Here we de- channel conductance to gene expression. Hydrolysis of 3’,5’- scribe the distribution of the PDEl Bl (63 kDa) CaM-depen- cyclic nucleotidesto 5’-nucleosidemonophosphates is the major dent PDE in mouse brain. An anti-peptide antiserum to this mechanismfor decreasingintracellular cyclic nucleotide levels. isoform immunoprecipitated -3O-40% of cytosolic PDE ac- This reaction is catalyzed by cyclic nucleotide phosphodiester- tivity, whereas antiserum to PDElA2 (61 kDa isoform) re- ase (PDE) enzymes that constitute a large superfamily (Beavo moved 60-70%, demonstrating that these isoforms are the and Reifsynder, 1990).
    [Show full text]
  • Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding Rnas
    Review Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding RNAs Yu Zhang †, Jun Li †, Xing-Ning Lai, Xue-Qiao Jiao, Jun-Ping Xiong and Li-Xia Xiong * Department of Pathophysiology, Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Medical College, Nanchang University, 461 Bayi Road, Nanchang 330006, China; [email protected] (Y.Z.); [email protected] (J.L.); [email protected] (X.-N.L.); [email protected] (X.-Q.J.); [email protected] (J.-P.X.) * Correspondence: [email protected]; Tel.: +86-791-8636-0556 † These authors contributed equally to this work. Received: 30 December 2018; Accepted: 8 February 2019; Published: 11 February 2019 Abstract: Breast cancer is the most common malignant tumors in females. Although the conventional treatment has demonstrated a certain effect, some limitations still exist. The Rho guanosine triphosphatase (GTPase) Cdc42 (Cell division control protein 42 homolog) is often upregulated by some cell surface receptors and oncogenes in breast cancer. Cdc42 switches from inactive guanosine diphosphate (GDP)-bound to active GTP-bound though guanine-nucleotide- exchange factors (GEFs), results in activation of signaling cascades that regulate various cellular processes such as cytoskeletal changes, proliferation and polarity establishment. Targeting Cdc42 also provides a strategy for precise breast cancer therapy. In addition, Cdc42 is a potential target for several types of non-coding RNAs including microRNAs and lncRNAs. These non-coding RNAs is extensively involved in Cdc42-induced tumor processes, while many of them are aberrantly expressed. Here, we focus on the role of Cdc42 in cell morphogenesis, proliferation, motility, angiogenesis and survival, introduce the Cdc42-targeted non-coding RNAs, as well as present current development of effective Cdc42-targeted inhibitors in breast cancer.
    [Show full text]
  • Role of Rac1-Pak Pathway in Aggressive B-Cell Lymphoma
    University of Nebraska Medical Center DigitalCommons@UNMC Theses & Dissertations Graduate Studies Spring 5-4-2019 Role of Rac1-Pak pathway in aggressive b-cell lymphoma Tian Tian University of Nebraska Medical Center Follow this and additional works at: https://digitalcommons.unmc.edu/etd Part of the Hemic and Lymphatic Diseases Commons, and the Neoplasms Commons Recommended Citation Tian, Tian, "Role of Rac1-Pak pathway in aggressive b-cell lymphoma" (2019). Theses & Dissertations. 344. https://digitalcommons.unmc.edu/etd/344 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@UNMC. It has been accepted for inclusion in Theses & Dissertations by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. i Role of Rac1-PAK Pathway in Aggressive B-cell Lymphomas By Tian Tian A DISSERTATION Presented to the Faculty of The University of Nebraska Graduate College in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Pathology & Microbiology Graduate program Under the Supervision of Professor Kai Fu University of Nebraska Medical Center, Omaha, Nebraska Dec, 2018 Supervisory Committee: Ying Yan, Ph.D. John S Davis, Ph.D. Timothy C Greiner, M.D. Javeed Iqbal, Ph.D. ii Role of Rac1-PAK pathway in Aggressive B-cell Lymphomas Tian Tian University of Nebraska Medical Center, 2018 Advisor: Kai Fu, M.D. Ph.D. Aggressive B-cell lymphomas are diverse group of neoplasms that arise at different stages of B-cell development and by various mechanisms of neoplastic transformation. Aggressive B-cell lymphomas include many types, subtypes and variants of diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), mantle cell lymphoma (MCL) and B lymphoblastic lymphoma.
    [Show full text]
  • Compartment-Specific Phosphorylation of Phosducin In
    Faculty Scholarship 2007 Compartment-specific hoP sphorylation of Phosducin in Rods Underlies Adaptation to Various Levels of Illumination Hongman Song Marycharmain Belcastro E. J. Young Maxim Sokolov Follow this and additional works at: https://researchrepository.wvu.edu/faculty_publications Digital Commons Citation Song, Hongman; Belcastro, Marycharmain; Young, E. J.; and Sokolov, Maxim, "Compartment-specific hospP horylation of Phosducin in Rods Underlies Adaptation to Various Levels of Illumination" (2007). Faculty Scholarship. 92. https://researchrepository.wvu.edu/faculty_publications/92 This Article is brought to you for free and open access by The Research Repository @ WVU. It has been accepted for inclusion in Faculty Scholarship by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 282, NO. 32, pp. 23613–23621, August 10, 2007 © 2007 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A. Compartment-specific Phosphorylation of Phosducin in Rods Underlies Adaptation to Various Levels of Illumination* Received for publication, March 7, 2007, and in revised form, June 11, 2007 Published, JBC Papers in Press, June 14, 2007, DOI 10.1074/jbc.M701974200 Hongman Song, Marycharmain Belcastro, E. J. Young, and Maxim Sokolov1 From the Departments of Ophthalmology and Biochemistry, West Virginia University School of Medicine and West Virginia University Eye Institute, Morgantown, West Virginia 26506 Phosducin is a major phosphoprotein of rod photoreceptors specific complex with the ␤␥ subunits of visual heterotrimeric that interacts with the G␤␥ subunits of heterotrimeric G pro- G protein, transducin (4, 5), and other heterotrimeric G pro- teins in its dephosphorylated state.
    [Show full text]
  • Diverse Physiological Functions for Dual-Specificity MAP Kinase
    Commentary 4607 Diverse physiological functions for dual-specificity MAP kinase phosphatases Robin J. Dickinson and Stephen M. Keyse* Cancer Research UK Stress Response Laboratory, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK *Author for correspondence (e-mail: [email protected]) Accepted 19 September 2006 Journal of Cell Science 119, 4607-4615 Published by The Company of Biologists 2006 doi:10.1242/jcs.03266 Summary A structurally distinct subfamily of ten dual-specificity functions in mammalian cells and tissues. However, recent (Thr/Tyr) protein phosphatases is responsible for the studies employing a range of model systems have begun to regulated dephosphorylation and inactivation of mitogen- reveal essential non-redundant roles for the MKPs in activated protein kinase (MAPK) family members in determining the outcome of MAPK signalling in a variety mammals. These MAPK phosphatases (MKPs) interact of physiological contexts. These include development, specifically with their substrates through a modular kinase- immune system function, metabolic homeostasis and the interaction motif (KIM) located within the N-terminal non- regulation of cellular stress responses. Interestingly, these catalytic domain of the protein. In addition, MAPK binding functions may reflect both restricted subcellular MKP is often accompanied by enzymatic activation of the C- activity and changes in the levels of signalling through terminal catalytic domain, thus ensuring specificity of multiple MAPK pathways. action. Despite our knowledge of the biochemical and structural basis for the catalytic mechanism of the MKPs, we know much less about their regulation and physiological Key words: MAPK, MKP, Signal transduction, Phosphorylation Introduction the activation motif is required for MAPK activity, Mitogen-activated protein kinases (MAPKs) constitute a dephosphorylation of either residue inactivates these enzymes.
    [Show full text]