Supplement Table 2: Genes encoding ERK pathway components and
some of known direct ERK targets
Abbreviation and gene
description
Official symbol and name:
Locus
ERK pathway components
RAF1: v-raf-1 murine
3p25
leukemia viral oncogene
homolog 1
BRAF: v-raf murine
7q34
sarcoma viral oncogene
homolog B1
MAP2K1: mitogen-activated 15q22.1protein kinase kinase 1
q22.33
MAP2K2: mitogen-activated 19p13.3
protein kinase kinase 2
MAPK3: mitogen-activated 16p11.2
protein kinase
MAPK1: mitogen-activated 22q11.21a
protein kinase 1
Some of known direct ERK targets
RSK1: Ribosomal
RPS6KA1: ribosomal
1p36.11a
protein S6 kinase 1
protein S6 kinase, 90kDa,
polypeptide 1
RSK2: Ribosomal
RPS6KA2: ribosomal
6q27
protein S6 kinase 2
protein S6 kinase, 90kDa,
polypeptide 2
RSK3: Ribosomal
RPS6KA3: ribosomal
Xp22.2protein S6 kinase 3
protein S6 kinase, 90kDa,
p22.1a
polypeptide 3
MSK1: Mitogen- and
RPS6KA5: ibosomal protein 14q31stress-activated protein
S6 kinase, 90kDa,
q32.1
kinase-1
polypeptide 5
MSK2: Mitogen- and
RPS6KA6: ribosomal
Xq21
stress-activated protein
protein S6 kinase, 90kDa,
kinase-2
polypeptide 6
CRY1:Cryptochrome-1 CRY1:Cryptochrome-1
12q23q24.1
(9)
CRY2: Cryptochrome-2 CRY21:Cryptochrome-2
11p11.2
(9)
BMAL1: brain and
ARNTL: aryl hydrocarbon
11p15
muscle Arnt-like protein receptor nuclear translocator1
like
Raf-1: v-raf-1 murine
leukemia viral oncogene
homolog 1
B-Raf: v-raf murine
sarcoma viral oncogene
homolog B1
MEK1: MAPK/ERK
kinase 1
MEK2: MAPK/ERK
kinase 2
ERK1: extracellular
signal-regulated kinase 1
ERK2: Extracellular
signal-regulated kinase 2
Genes or loci
implicated in
mood disorder
genetic studies
No
Yes (1)
No
Yes (2, 3)
No
Yes (2, 4-6)
Yes (7)
No
Yes (8)
No
No
Yes (10)
Yes (11)
Yes (13); (1418)
(12)
I-2: Phosphatase
Inhibitor-2
(19)
Spinophilin or
neurabin II
(21)
ELK1
HDAC4: histone
deacetylase 4
(22)
Synapsin I
(23)
Kv4.2: POTASSIUM
VOLTAGE-GATED
CHANNEL, SHALRELATED
SUBFAMILY,
MEMBER 2; KCND2
(24)
GABAA alpha 1
receptor
(25)
PPP1R2: protein
phosphatase 1, regulatory
(inhibitor) subunit 2
PPP1R9B: protein
phosphatase 1, regulatory
subunit 9B, spinophilin
ELK1: ELK1, member of
ETS oncogene family
HDAC4: histone deacetylase
4
3q29
Yes (20)
17q21.33
No
Xp11.2
No
2q37.2
No
SYN1
Xp11.23
MAO-B
7q31
No
5q34-q35
Yes (26, 27)
KCND2: potassium voltagegated channel, Shal-related
subfamily, member 2
GABRA1: gammaaminobutyric acid (GABA)
A receptor, alpha
Yes (4)
References:
1.
Liu J, Juo SH, Dewan A, Grunn A, Tong X, Brito M et al. Evidence for a putative
bipolar disorder locus on 2p13-16 and other potential loci on 4q31, 7q34, 8q13,
9q31, 10q21-24, 13q32, 14q21 and 17q11-12. Molecular psychiatry 2003 Mar;
8(3): 333-342.
2.
Hamshere ML, Bennett P, Williams N, Segurado R, Cardno A, Norton N et al.
Genomewide linkage scan in schizoaffective disorder: significant evidence for
linkage at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19p13.
Archives of general psychiatry 2005 Oct; 62(10): 1081-1088.
3.
Cheng R, Juo SH, Loth JE, Nee J, Iossifov I, Blumenthal R et al. Genome-wide
linkage scan in a large bipolar disorder sample from the National Institute of
Mental Health genetics initiative suggests putative loci for bipolar disorder,
psychosis, suicide, and panic disorder. Molecular psychiatry 2006 Mar; 11(3):
252-260.
4.
Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR,
Turner G et al. A high-density genome scan detects evidence for a bipolar-
2
disorder susceptibility locus on 13q32 and other potential loci on 1q32 and
18p11.2. Proceedings of the National Academy of Sciences of the United States of
America 1999 May 11; 96(10): 5604-5609.
5.
Potash JB, Willour VL, Chiu YF, Simpson SG, MacKinnon DF, Pearlson GD et
al. The familial aggregation of psychotic symptoms in bipolar disorder pedigrees.
The American journal of psychiatry 2001 Aug; 158(8): 1258-1264.
6.
Badenhop RF, Moses MJ, Scimone A, Mitchell PB, Ewen-White KR, Rosso A et
al. A genome screen of 13 bipolar affective disorder pedigrees provides evidence
for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19.
Molecular psychiatry 2002; 7(8): 851-859.
7.
McGuffin P, Knight J, Breen G, Brewster S, Boyd PR, Craddock N et al. Whole
genome linkage scan of recurrent depressive disorder from the depression
network study. Human molecular genetics 2005 Nov 15; 14(22): 3337-3345.
8.
Stine OC, McMahon FJ, Chen L, Xu J, Meyers DA, MacKinnon DF et al. Initial
genome screen for bipolar disorder in the NIMH genetics initiative pedigrees:
chromosomes 2, 11, 13, 14, and X. American journal of medical genetics 1997
May 31; 74(3): 263-269.
9.
Sanada K, Harada Y, Sakai M, Todo T, Fukada Y. Serine phosphorylation of
mCRY1 and mCRY2 by mitogen-activated protein kinase. Genes Cells 2004
Aug; 9(8): 697-708.
10.
Kato T. Molecular genetics of bipolar disorder and depression. Psychiatry and
clinical neurosciences 2007 Feb; 61(1): 3-19.
11.
Middleton FA, Pato MT, Gentile KL, Morley CP, Zhao X, Eisener AF et al.
Genomewide linkage analysis of bipolar disorder by use of a high-density singlenucleotide-polymorphism (SNP) genotyping assay: a comparison with
microsatellite marker assays and finding of significant linkage to chromosome
6q22. American journal of human genetics 2004 May; 74(5): 886-897.
12.
Sanada K, Okano T, Fukada Y. Mitogen-activated protein kinase phosphorylates
and negatively regulates basic helix-loop-helix-PAS transcription factor BMAL1.
The Journal of biological chemistry 2002 Jan 4; 277(1): 267-271.
13.
Mitchell P, Waters B, Morrison N, Shine J, Donald J, Eisman J. Close linkage of
bipolar disorder to chromosome 11 markers is excluded in two large Australian
pedigrees. Journal of affective disorders 1991 Jan; 21(1): 23-32.
14.
Kelsoe JR, Kristbjanarson H, Bergesch P, Shilling P, Hirsch S, Mirow A et al. A
genetic linkage study of bipolar disorder and 13 markers on chromosome 11
3
including the D2 dopamine receptor. Neuropsychopharmacology 1993 Dec; 9(4):
293-301.
15.
Law A, Richard CW, 3rd, Cottingham RW, Jr., Lathrop GM, Cox DR, Myers
RM. Genetic linkage analysis of bipolar affective disorder in an Old Order Amish
pedigree. Human genetics 1992 Mar; 88(5): 562-568.
16.
McQuillin A, Lawrence J, Curtis D, Kalsi G, Smyth C, Hannesdottir S et al.
Adjacent genetic markers on chromosome 11p15.5 at or near the tyrosine
hydroxylase locus that show population linkage disequilibrium with each other do
not show allelic association with bipolar affective disorder. Psychological
medicine 1999 Nov; 29(6): 1449-1454.
17.
McInnis MG, Dick DM, Willour VL, Avramopoulos D, MacKinnon DF, Simpson
SG et al. Genome-wide scan and conditional analysis in bipolar disorder:
evidence for genomic interaction in the National Institute of Mental Health
genetics initiative bipolar pedigrees. Biological psychiatry 2003 Dec 1; 54(11):
1265-1273.
18.
Zandi PP, Willour VL, Huo Y, Chellis J, Potash JB, MacKinnon DF et al.
Genome scan of a second wave of NIMH genetics initiative bipolar pedigrees:
chromosomes 2, 11, 13, 14, and X. Am J Med Genet B Neuropsychiatr Genet
2003 May 15; 119(1): 69-76.
19.
Wang QM, Guan KL, Roach PJ, DePaoli-Roach AA. Phosphorylation and
activation of the ATP-Mg-dependent protein phosphatase by the mitogenactivated protein kinase. The Journal of biological chemistry 1995 Aug 4;
270(31): 18352-18358.
20.
Schosser A, Fuchs K, Leisch F, Bailer U, Meszaros K, Lenzinger E et al. Possible
linkage of schizophrenia and bipolar affective disorder to chromosome 3q29; a
follow-up. Journal of psychiatric research 2004 May-Jun; 38(3): 357-364.
21.
Futter M, Uematsu K, Bullock SA, Kim Y, Hemmings HC, Jr., Nishi A et al.
Phosphorylation of spinophilin by ERK and cyclin-dependent PK 5 (Cdk5).
Proceedings of the National Academy of Sciences of the United States of America
2005 Mar 1; 102(9): 3489-3494.
22.
Zhou X, Richon VM, Wang AH, Yang XJ, Rifkind RA, Marks PA. Histone
deacetylase 4 associates with extracellular signal-regulated kinases 1 and 2, and
its cellular localization is regulated by oncogenic Ras. Proceedings of the
National Academy of Sciences of the United States of America 2000 Dec 19;
97(26): 14329-14333.
4
23.
Yamagata Y, Jovanovic JN, Czernik AJ, Greengard P, Obata K. Bidirectional
changes in synapsin I phosphorylation at MAP kinase-dependent sites by acute
neuronal excitation in vivo. Journal of neurochemistry 2002 Mar; 80(5): 835-842.
24.
Adams JP, Anderson AE, Varga AW, Dineley KT, Cook RG, Pfaffinger PJ et al.
The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated
protein kinase ERK. Journal of neurochemistry 2000 Dec; 75(6): 2277-2287.
25.
Bell-Horner CL, Dohi A, Nguyen Q, Dillon GH, Singh M. ERK/MAPK pathway
regulates GABAA receptors. Journal of neurobiology 2006 Nov; 66(13): 14671474.
26.
Yamada K, Watanabe A, Iwayama-Shigeno Y, Yoshikawa T. Evidence of
association between gamma-aminobutyric acid type A receptor genes located on
5q34 and female patients with mood disorders. Neuroscience letters 2003 Sep 25;
349(1): 9-12.
27.
Horiuchi Y, Nakayama J, Ishiguro H, Ohtsuki T, Detera-Wadleigh SD, Toyota T
et al. Possible association between a haplotype of the GABA-A receptor alpha 1
subunit gene (GABRA1) and mood disorders. Biological psychiatry 2004 Jan 1;
55(1): 40-45.
5