title: Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders.
abstract: Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase that modulates key signaling molecules involved in synaptic plasticity and neuronal function. Targets include extracellular-regulated kinase 1 and 2 (ERK1/2), stress-activated protein kinase p38 (p38), the Src family tyrosine kinase Fyn, N-methyl-D-aspartate receptors (NMDARs), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). STEP-mediated dephosphorylation of ERK1/2, p38, and Fyn leads to inactivation of these enzymes, whereas STEP-mediated dephosphorylation of surface NMDARs and AMPARs promotes their endocytosis. Accordingly, the current model of STEP function posits that it opposes long-term potentiation and promotes long-term depression. Phosphorylation, cleavage, dimerization, ubiquitination, and local translation all converge to maintain an appropriate balance of STEP in the central nervous system. Accumulating evidence over the past decade indicates that STEP dysregulation contributes to the pathophysiology of several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, fragile X syndrome, epileptogenesis, alcohol-induced memory loss, Huntington's disease, drug abuse, stroke/ischemia, and inflammatory pain. This comprehensive review discusses STEP expression and regulation and highlights how disrupted STEP function contributes to the pathophysiology of diverse neuropsychiatric disorders.
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Goebel-Goody
authors.forename: Matthew
authors.initials: M
authors.lastname: Baum
authors.forename: Constantinos D
authors.initials: CD
authors.lastname: Paspalas
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Fernandez
authors.forename: Niki C
authors.initials: NC
authors.lastname: Carty
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kurup
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lombroso
mesh_terms: D001921:Brain / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D009422:Nervous System Diseases / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013379:Substrate Specificity
chemical_list: C489930:PTPN5 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor
references.citation: Curr Opin Pharmacol. 2006 Feb;6(1):68-74
references.pmid: 16376149
references.citation: Nat Med. 2011 Apr;17(4):470-8
references.pmid: 21441918
references.citation: Nat Neurosci. 2002 May;5(5):405-14
references.pmid: 11953750
references.citation: Brain Res Mol Brain Res. 1995 Jul;31(1-2):165-72
references.pmid: 7476025
references.citation: Curr Opin Neurobiol. 2004 Jun;14(3):311-7
references.pmid: 15194111
references.citation: J Neurosci. 2004 Oct 20;24(42):9425-33
references.pmid: 15496678
references.citation: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7746-50
references.pmid: 12032354
references.citation: Nat Rev Neurosci. 2010 Oct;11(10):682-96
references.pmid: 20842175
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4507-12
references.pmid: 19240213
references.citation: Biochem Biophys Res Commun. 2011 Jul 8;410(3):377-81
references.pmid: 21683066
references.citation: Proc Natl Acad Sci U S A. 1981 Oct;78(10):6013-7
references.pmid: 6273838
references.citation: Neuroscience. 2009 Feb 18;158(4):1446-59
references.pmid: 19041929
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2008 Oct 5;147B(7):1253-7
references.pmid: 18452182
references.citation: AMA Arch Gen Psychiatry. 1959 Dec;1:651-6
references.pmid: 14438905
references.citation: Proc Natl Acad Sci U S A. 1988 Aug;85(15):5733-7
references.pmid: 2456581
references.citation: Neuron. 2005 Mar 3;45(5):675-88
references.pmid: 15748844
references.citation: Mol Psychiatry. 1996 Jul;1(3):190-9
references.pmid: 9118343
references.citation: J Neurosci. 2000 Aug 15;20(16):5924-31
references.pmid: 10934239
references.citation: J Neurosci. 1993 May;13(5):2264-72
references.pmid: 8478698
references.citation: Neurobiol Learn Mem. 1999 Jul;72(1):8-12
references.pmid: 10371711
references.citation: Neuron. 1998 Nov;21(5):1129-39
references.pmid: 9856468
references.citation: J Neurochem. 2011 Mar;116(6):1097-111
references.pmid: 21198639
references.citation: Science. 2002 Oct 25;298(5594):789-91
references.pmid: 12399581
references.citation: Am J Psychiatry. 2000 Nov;157(11):1811-23
references.pmid: 11058479
references.citation: Eur J Neurosci. 2001 Nov;14(9):1492-504
references.pmid: 11722611
references.citation: BMC Med. 2010 Dec 22;8:89
references.pmid: 21176189
references.citation: J Biol Chem. 1998 Jun 19;273(25):15366-72
references.pmid: 9624118
references.citation: J Neurochem. 2010 Dec;115(6):1350-62
references.pmid: 21029094
references.citation: Science. 1987 Jan 2;235(4784):73-6
references.pmid: 2879352
references.citation: Cell. 2001 Nov 16;107(4):489-99
references.pmid: 11719189
references.citation: Synapse. 2009 Jan;63(1):69-81
references.pmid: 18932218
references.citation: J Neurosci. 2005 Mar 30;25(13):3294-303
references.pmid: 15800184
references.citation: J Neurosci. 2005 Oct 19;25(42):9694-703
references.pmid: 16237174
references.citation: Mol Brain. 2010 Jan 21;3:4
references.pmid: 20180987
references.citation: Nat Med. 2006 Jul;12(7):824-8
references.pmid: 16767099
references.citation: Neuroscience. 1995 Dec;69(3):869-80
references.pmid: 8596655
references.citation: Cancer Res. 1992 Feb 1;52(3):737-40
references.pmid: 1370651
references.citation: Nat Neurosci. 2010 Jan;13(1):76-83
references.pmid: 19915563
references.citation: J Neurochem. 2007 Oct;103(2):531-41
references.pmid: 17623046
references.citation: Hippocampus. 2000;10(1):122-30
references.pmid: 10706223
references.citation: Science. 1989 Mar 31;243(4899):1721-4
references.pmid: 2467382
references.citation: Am J Psychiatry. 2000 Jul;157(7):1141-9
references.pmid: 10873924
references.citation: Science. 1999 Jul 9;285(5425):215-20
references.pmid: 10398591
references.citation: Biochem J. 2003 May 15;372(Pt 1):193-201
references.pmid: 12583813
references.citation: Nat Neurosci. 2004 Sep;7(9):917-8
references.pmid: 15322548
references.citation: Nat Neurosci. 2001 Aug;4(8):794-802
references.pmid: 11477425
references.citation: Neuron. 2010 Jun 10;66(5):768-80
references.pmid: 20547133
references.citation: J Neurosci. 2003 Jul 30;23(17):6754-8
references.pmid: 12890768
references.citation: Neuron. 2002 Mar 28;34(1):127-38
references.pmid: 11931747
references.citation: Brain Res Dev Brain Res. 1996 Feb 26;91(2):190-9
references.pmid: 8852369
references.citation: Annu Rev Pharmacol Toxicol. 2002;42:209-34
references.pmid: 11807171
references.citation: Neuron. 2009 Jan 15;61(1):10-26
references.pmid: 19146809
references.citation: Eur J Neurosci. 2003 Sep;18(6):1706-10
references.pmid: 14511349
references.citation: J Neurosci. 2010 Apr 28;30(17):5948-57
references.pmid: 20427654
references.citation: Science. 2002 Jul 19;297(5580):353-6
references.pmid: 12130773
references.citation: J Intellect Disabil Res. 2008 Jun;52(Pt 6):469-82
references.pmid: 18444988
references.citation: J Neurosci. 2001 Jun 15;21(12):4125-33
references.pmid: 11404397
references.citation: Nat Neurosci. 2001 Nov;4(11):1079-85
references.pmid: 11687813
references.citation: Future Med Chem. 2010 Oct;2(10):1563-76
references.pmid: 21426149
references.citation: J Neurochem. 2011 Jan;116(1):93-104
references.pmid: 21054385
references.citation: Eur J Neurosci. 2006 Jun;23(11):2847-56
references.pmid: 16819973
references.citation: Cereb Cortex. 2009 Jul;19(7):1666-77
references.pmid: 19029061
references.citation: Cerebellum. 2009 Jun;8(2):80-8
references.pmid: 19137382
references.citation: Cell. 2003 Feb 7;112(3):317-27
references.pmid: 12581522
references.citation: J Neurosci. 2000 Sep 1;20(17):6385-93
references.pmid: 10964944
references.citation: J Neurosci. 1996 Dec 15;16(24):7821-31
references.pmid: 8987810
references.citation: Nat Neurosci. 2003 Jan;6(1):34-42
references.pmid: 12483215
references.citation: J Neurochem. 1999 Nov;73(5):1995-2001
references.pmid: 10537058
references.citation: Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7242-6
references.pmid: 1714595
references.citation: Curr Pharm Des. 2008;14(4):359-70
references.pmid: 18289062
references.citation: Neuron. 2002 Oct 24;36(3):435-49
references.pmid: 12408846
references.citation: Curr Opin Cell Biol. 1997 Apr;9(2):180-6
references.pmid: 9069255
references.citation: J Neurosci. 2000 Aug 1;20(15):5630-8
references.pmid: 10908600
references.citation: FASEB J. 2008 Dec;22(12):4258-71
references.pmid: 18711223
references.citation: Neuron. 2008 Oct 23;60(2):201-14
references.pmid: 18957214
references.citation: Am J Psychiatry. 1991 Oct;148(10):1301-8
references.pmid: 1654746
references.citation: J Neurosci. 2000 Dec 1;20(23):8701-9
references.pmid: 11102476
references.citation: Cell. 2008 Feb 8;132(3):434-48
references.pmid: 18267074
references.citation: J Biol Chem. 2003 Mar 28;278(13):11020-5
references.pmid: 12536146
references.citation: Biol Psychiatry. 2007 May 1;61(9):1049-61
references.pmid: 17081505
references.citation: Acta Pharmacol Sin. 2011 Jul;32(7):861-72
references.pmid: 21685929
references.citation: Nucleic Acids Res. 2001 Jun 1;29(11):2276-83
references.pmid: 11376146
references.citation: Neurobiol Dis. 2009 Dec;36(3):461-9
references.pmid: 19733666
references.citation: Epilepsia. 2011 Mar;52(3):497-506
references.pmid: 21204826
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15201-6
references.pmid: 15475576
references.citation: Neuron. 2003 Feb 20;37(4):555-8
references.pmid: 12597853
references.citation: Biochem J. 2006 May 1;395(3):483-91
references.pmid: 16441242
references.citation: J Neurosci. 1997 Jul 1;17(13):5062-9
references.pmid: 9185543
references.citation: Sci Signal. 2008 Jun 03;1(22):re4
references.pmid: 18523239
references.citation: J Biol Chem. 2002 Jul 5;277(27):24274-9
references.pmid: 11983687
references.citation: Eur J Neurosci. 2008 May;27(9):2444-52
references.pmid: 18445231
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6650-5
references.pmid: 21464302
references.citation: J Neurosci. 2004 Aug 25;24(34):7482-90
references.pmid: 15329395
references.citation: Eur J Cell Biol. 1997 Apr;72(4):337-44
references.pmid: 9127733
references.citation: J Neurol Neurosurg Psychiatry. 2004 Sep;75 Suppl 3:iii16-21
references.pmid: 15316040
references.citation: J Neurosci. 2009 Jul 22;29(29):9330-43
references.pmid: 19625523
references.citation: J Alzheimers Dis. 2011;24(4):633-42
references.pmid: 21321401
references.citation: Lancet Neurol. 2011 Jan;10(1):83-98
references.pmid: 21163446
references.citation: Int J Neuropsychopharmacol. 2009 Aug;12(7):873-83
references.pmid: 19154630
references.citation: Trends Neurosci. 2004 Jul;27(7):370-7
references.pmid: 15219735
references.citation: Nature. 1995 Sep 28;377(6547):344-8
references.pmid: 7566089
references.citation: J Neurochem. 2005 Apr;93(1):186-94
references.pmid: 15773918
references.citation: Brain Res Mol Brain Res. 1995 Aug;32(1):87-93
references.pmid: 7494467
references.citation: J Neurosci. 2006 Mar 1;26(9):2544-54
references.pmid: 16510732
references.citation: Nat Neurosci. 2005 Aug;8(8):1051-8
references.pmid: 16025111
references.citation: Genes Dev. 2003 Mar 1;17(5):638-53
references.pmid: 12629046
references.citation: J Neurosci. 2003 Nov 5;23(31):10093-9
references.pmid: 14602824
references.citation: Am J Psychiatry. 2001 Sep;158(9):1367-77
references.pmid: 11532718
references.citation: J Neurosci. 1997 Apr 15;17(8):2921-7
references.pmid: 9092613
references.citation: Neurochem Int. 2007 Jul-Sep;51(2-4):173-84
references.pmid: 17669558
references.citation: Synapse. 2011 Jan;65(1):54-63
references.pmid: 20506566
references.citation: Biol Psychiatry. 2009 Apr 15;65(8):637-45
references.pmid: 19026408
references.citation: Eur J Neurosci. 2011 Jun;33(12):2288-98
references.pmid: 21501258
references.citation: Science. 2000 May 19;288(5469):1254-7
references.pmid: 10818003
references.citation: J Neurochem. 1999 Nov;73(5):1990-4
references.pmid: 10537057
references.citation: J Neurosci. 2000 Nov 1;20(21):8177-87
references.pmid: 11050141
references.citation: Nat Methods. 2005 Jan;2(1):17-25
references.pmid: 15789031
references.citation: Cell. 2006 Oct 6;127(1):49-58
references.pmid: 17018276
references.citation: Neuron. 1996 Mar;16(3):611-7
references.pmid: 8785058
references.citation: Biochem J. 2010 Aug 1;429(3):403-17
references.pmid: 20626350
references.citation: Mol Med Today. 2000 Mar;6(3):133-5
references.pmid: 10689317
references.citation: J Pharmacol Exp Ther. 2010 Mar;332(3):720-9
references.pmid: 20008487
references.citation: J Neurosci. 2004 Jul 7;24(27):6152-60
references.pmid: 15240807
references.citation: Br J Psychiatry Suppl. 2001 Apr;40:s18-24
references.pmid: 11315219
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15625-30
references.pmid: 20713712
references.citation: Mol Cell Neurosci. 2009 Feb;40(2):267-79
references.pmid: 19063969
references.citation: Nat Rev Neurosci. 2007 Sep;8(9):687-99
references.pmid: 17704811
references.citation: J Neurosci. 1995 Feb;15(2):1532-44
references.pmid: 7869116
references.citation: J Neurochem. 2010 Aug;114(4):1107-18
references.pmid: 20524968
references.citation: Trends Pharmacol Sci. 2006 Oct;27(10):525-30
references.pmid: 16919785
references.citation: EMBO J. 2006 Jun 21;25(12):2867-77
references.pmid: 16710293
references.citation: J Neurosci. 2007 Apr 25;27(17):4519-29
references.pmid: 17460065
references.citation: Epilepsia. 2011 Jan;52 Suppl 1:1-6
references.pmid: 21214533
references.citation: J Cell Biol. 2003 Jul 7;162(1):113-24
references.pmid: 12847086
references.citation: Mol Cell Neurosci. 2004 Dec;27(4):404-16
references.pmid: 15555919
references.citation: J Neurosci. 2008 Oct 15;28(42):10561-6
references.pmid: 18923032
references.citation: Alcohol Clin Exp Res. 1997 May;21(3):404-8
references.pmid: 9161598
references.citation: Annu Rev Neurosci. 2002;25:409-32
references.pmid: 12052915
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4429-34
references.pmid: 18332424
references.citation: Cardiovasc Res. 1998 Jul;39(1):106-20
references.pmid: 9764193
references.citation: Cell. 2011 Jul 22;146(2):247-61
references.pmid: 21784246
references.citation: Cell. 1993 Mar 26;72(6):971-83
references.pmid: 8458085
references.citation: Stroke. 2011 May;42(5):1495-9
references.pmid: 21474803
references.citation: Nat Neurosci. 2004 Jun;7(6):635-42
references.pmid: 15133516
references.citation: Exp Neurol. 1997 May;145(1):228-34
references.pmid: 9184124
references.citation: J Physiol. 2006 May 1;572(Pt 3):789-98
references.pmid: 16513670
references.citation: J Neurosci. 2004 Nov 10;24(45):10191-200
references.pmid: 15537891
references.citation: J Neurosci. 2001 Feb 15;21(4):1327-33
references.pmid: 11160403
references.citation: Nature. 1999 Sep 2;401(6748):63-9
references.pmid: 10485705
references.citation: J Neurosci. 1993 Jul;13(7):3064-74
references.pmid: 8331384
references.citation: Neuroscience. 2000;95(3):913-22
references.pmid: 10670458
references.citation: Psychopharmacology (Berl). 2009 Sep;205(4):529-64
references.pmid: 19455309
references.citation: Arch Gen Psychiatry. 1994 Mar;51(3):199-214
references.pmid: 8122957
references.citation: Glia. 2000 Feb 15;29(4):316-29
references.pmid: 10652442
references.citation: J Biol Chem. 2004 Aug 27;279(35):37069-78
references.pmid: 15229225
references.citation: Neuron. 2001 Feb;29(2):485-96
references.pmid: 11239437
references.citation: J Neurochem. 2006 Sep;98(6):1798-809
references.pmid: 16899073
references.citation: J Biol Chem. 2001 Jan 5;276(1):693-9
references.pmid: 11024032
references.citation: J Neurosci. 2000 Jun 15;20(12):4563-72
references.pmid: 10844026
references.citation: J Neurosci. 2008 Apr 16;28(16):4216-30
references.pmid: 18417701
references.citation: Neuron. 2006 Aug 17;51(4):441-54
references.pmid: 16908410
references.citation: Behav Brain Res. 1983 Sep;9(3):315-35
references.pmid: 6639740
references.citation: J Neurosci. 2007 Mar 14;27(11):2999-3009
references.pmid: 17360923
references.citation: J Neurosci. 2011 Jun 1;31(22):8150-62
references.pmid: 21632937
references.citation: Neuron. 2010 Feb 25;65(4):445-59
references.pmid: 20188650
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):19014-9
references.pmid: 20956308
references.citation: Exp Neurol. 2008 Nov;214(1):69-77
references.pmid: 18708052
references.citation: J Neurosci. 2010 Aug 11;30(32):10624-38
references.pmid: 20702695
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):491-6
references.pmid: 15608059
references.citation: Front Mol Neurosci. 2008 Mar 28;1:4
references.pmid: 18946537
references.citation: Learn Mem. 2010 Jun 21;17(7):314-27
references.pmid: 20566674
references.citation: Am J Hum Genet. 2002 Oct;71(4):877-92
references.pmid: 12145742
references.citation: J Neurochem. 2010 Dec;115(5):1112-22
references.pmid: 20831600
references.citation: Brain Res. 1990 Dec 24;537(1-2):203-8
references.pmid: 2150775
references.citation: Nat Rev Neurosci. 2007 Oct;8(10):776-89
references.pmid: 17848965
references.citation: Neuropsychopharmacology. 2002 Oct;27(4):565-75
references.pmid: 12377393