KinaseNET

Nomenclature

Short Name:

GSK3A

Full Name:

Glycogen synthase kinase-3 alpha

Alias:

Classification

Type:

Protein-serine/threonine kinase

Group:

CMGC

Family:

GSK

SubFamily:

Specific Links

BioCarta Entry:	ptdins pathway
Entrez-Gene Entry:	2931
Entrez-Protein Entry:	NP_063937
GeneCards Entry:	GSK3A
KinBASE Entry:	GSK3A
Pfam Entry:	P49840
PhosphoNET Entry:	P49840
Phosphosite Plus Entry:	603
Protein Data Bank Entry:	2DFM
ScanSite Entry:	P49840
Source Entry:	GSK3A
UCSD-Nature Entry:	A001105
UniProt Entry:	P49840
Kinexus Products:	GSK3A Glycogen synthase-serine kinase 3 alpha pan-specific antibody AB-NK069-3 Glycogen synthase-serine kinase 3 alpha S278+Y279 phosphosite-specific antibody AB-PK647 Glycogen synthase-serine kinase 3 alpha T19+S21 phosphosite-specific antibody AB-PK648 Glycogen synthase-serine kinase 3 alpha Y279 phosphosite-specific antibody AB-PK649 Glycogen synthase-serine kinase 3 alpha Y284+Y285 phosphosite-specific antibody AB-PK650 Glycogen synthase-serine kinase 3 alpha (P88-T102, human) peptide - Powder PE-01BDA85 Glycogen synthase-serine kinase 3 alpha (S282-P288, human) pY284+pY285 phosphopeptide - Powder PE-04ABU95 Glycogen synthase-serine kinase 3 alpha (N276-S282, human) pY279 phosphopeptide - Powder PE-04ACX99 Glycogen synthase-serine kinase 3 alpha (R16-E24, human) pT19+pS21 phosphopeptide - Powder PE-04AMR99 Glycogen synthase-serine kinase 3 alpha (P275-P288, human) pS278+pY279+pS282+pY284+pY285 phosphopeptide - Powder PE-04AUQ95

General Links

Structure

Mol. Mass (Da):

50,981

# Amino Acids:

483

# mRNA Isoforms:

mRNA Isoforms:

50,981 Da (483 AA; P49840)

4D Structure:

Monomer. Interacts with ARRB2

3D Structure:

Download QuickTime Animation

1D Structure:

Retrieve Gene Sequence
Retrieve Full Protein Sequence
Retrieve Catalytic Domain Sequence

Subfamily Alignment

Domain Distribution:

Start	End	Domain

Kinexus Products

Click on entries below for direct links to relevant products from Kinexus for this protein kinase.

hiddentext

○	Glycogen synthase-serine kinase 3 alpha pan-specific antibody AB-NK069-3
○	Glycogen synthase-serine kinase 3 alpha S278+Y279 phosphosite-specific antibody AB-PK647
○	Glycogen synthase-serine kinase 3 alpha T19+S21 phosphosite-specific antibody AB-PK648
○	Glycogen synthase-serine kinase 3 alpha Y279 phosphosite-specific antibody AB-PK649
○	Glycogen synthase-serine kinase 3 alpha Y284+Y285 phosphosite-specific antibody AB-PK650
○	Glycogen synthase-serine kinase 3 alpha (P88-T102, human) peptide - Powder PE-01BDA85
○	Glycogen synthase-serine kinase 3 alpha (S282-P288, human) pY284+pY285 phosphopeptide - Powder PE-04ABU95
○	Glycogen synthase-serine kinase 3 alpha (N276-S282, human) pY279 phosphopeptide - Powder PE-04ACX99
○	Glycogen synthase-serine kinase 3 alpha (R16-E24, human) pT19+pS21 phosphopeptide - Powder PE-04AMR99
○	Glycogen synthase-serine kinase 3 alpha (P275-P288, human) pS278+pY279+pS282+pY284+pY285 phosphopeptide - Powder PE-04AUQ95

Post-translation Modifications

For detailed information on phosphorylation of this kinase go to PhosphoNET

Serine phosphorylated:

S2, S7, S14, S20, S21-, S39, S41, S52, S63, S72, S77, S97, S266, S278+, S282-.

Threonine phosphorylated:

T19, T46, T338, T340, T480.

Tyrosine phosphorylated:

Y134, Y177, Y180, Y197, Y220, Y226, Y279+, Y284-, Y285-, Y351.

Ubiquitinated:

K268, K355, K360.

Distribution

Based on gene microarray analysis from the NCBI

Human Tissue Distribution

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

69

907

32

1131
15

198

15

182
18

232

12

114
35

465

91

560
67

885

25

701
5

63

74

40
18

234

31

478
62

820

40

984
53

699

17

531
16

206

83

193
14

191

31

227
57

756

184

668
10

127

34

59
16

206

12

190
17

228

25

139
13

166

15

133
13

170

119

83
19

254

21

203
14

186

94

125
46

605

109

581
20

266

23

156
13

177

27

140
21

278

22

162
19

249

21

175
16

206

23

134
49

650

57

670
11

147

37

86
18

234

21

163
16

211

21

133
77

1011

28

599
24

314

24

243
100

1321

36

2330
6

82

72

209
63

836

57

731
12

163

35

180

Evolution

Species Conservation

PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:

100

100

100
99.6

99.8

100
99.8

99.8

100
-

-

96
-

-

98
85.5

86.3

96.5
-

-

-
93.9

95.5

95
97.1

97.7

97
-

-

-
-

-

-
67.9

75

-
67.5

74.5

86
71.8

77.6

88.5
-

-

-
33.5

38

-
64.2

75.2

-
55.3

63.8

-
-

-

-
-

-

-
24.4

38.1

-
-

-

67
52.8

63.8

67
40.8

55.5

59
-

-

70

For a wider analysis go to PhosphoNET Evolution in PhosphoNET

Regulation

Activation:

Phosphorylation at Thr-279 increases phosphotransferase activity and promotes nuclear localization.

Inhibition:

Phosphorylation at Ser-21 inhibits phosphotransferase activity.

Synthesis:

Degradation:

Known Upstream Kinases

For further details on these substrates click on the Substrate Short Name or UniProt ID. Phosphosite Location is hyperlinked to PhosphoNET predictions.

Based on in vitro and/or in vivo phosphorylation data

Kinase Short Name	UniProt ID (Human)	Phosphosite Location	Phosphosite Sequence	Effect of Phosphorylation

PKACa	P17612	S21	SGRARTSSFAEPGGG	-
Akt1	P31749	S21	SGRARTSSFAEPGGG	-
PKCz	Q05513	S21	SGRARTSSFAEPGGG	-
RSK2	P51812	S21	SGRARTSSFAEPGGG	-
PKCb	P05771	S21	SGRARTSSFAEPGGG	-
PKCd	Q05655	S21	SGRARTSSFAEPGGG	-
PKCb	P05771	S21	SGRARTSSFAEPGGG	-
PKCg	P05129	S21	SGRARTSSFAEPGGG	-
PKCh	P24723	S21	SGRARTSSFAEPGGG	-
MEK2	P36507	Y279	RGEPNVSYICSRYYR	+
MEK1	Q02750	Y279	RGEPNVSYICSRYYR	+
GSK3A	P49840	Y279	RGEPNVSYICSRYYR	+

Known Downstream Substrates

For further details on these substrates click on the Substrate Short Name or UniProt ID. Phosphosite Location is hyperlinked to PhosphoNET predictions.

Based on in vitro and/or in vivo phosphorylation data

Substrate Short Name	UniProt ID (Human)	Phosphosite Location	Phosphosite Sequence	Effect of Phosphorylation

ACLY	P53396	S451	STSTPAPSRTASFSE
ACLY	P53396	T447	NASGSTSTPAPSRTA
ANKRD28	O15084	S1040	INRYTNTSKTVSFEA
Axin	O15169	S486	LRTPGRQSPGPGHRS
Axin	O15169	T481	HVQRVLRTPGRQSPG
Bcl-3	P20749	S394	LSASPSSSPSQSPPR
Bcl-3	P20749	S398	PSSSPSQSPPRDPPG
C-EBPa	P49715	T226	HLQPGHPTPPPTPVP
C-EBPa	P49715	T230	GHPTPPPTPVPSPHP
CdGAP	Q9ULL6 Q2M1Z3	T790	PPAPPPPTPLEESTP
CREB1	P16220	S129	QKRREILSRRPSYRK	+
CRMP2 (DPYSL2)	Q16555	S518	KTVTPASSAKTSPAK
CTNNB1	P35222	S33	QQQSYLDSGIHSGAT	-
CTNNB1	P35222	S37	YLDSGIHSGATTTAP	?
CTNNB1	P35222	T41	GIHSGATTTAPSLSG	?
Cyclin D1 (CCND1)	P24385	T286	EEVDLACTPTDVRDV
Cyclin E1 (CCNE1)	P24864	T395	PLPSGLLTPPQSGKK
eIF2B-e	Q13144	S540	MDSEEPDSRGGSPQM	-
GSK3a	P49840	Y279	RGEPNVSYICSRYYR	+
IRS2	Q9Y4H2	S487	RPSSGSASASGSPSD
MAP2	P11137	S136	ETANLPPSPPPSPAS
MAP2	P11137	T1616	YSSRTPGTPGTPSYP
MAP2	P11137	T1619	RTPGTPGTPSYPRTP
MITF	O75030	S405	QARAHGLSLIPSTGL	+
MKI67IP (NIFK)	Q9BYG3	S230	TPEKTVDSQGPTPVC
MKI67IP (NIFK)	Q9BYG3	T234	TVDSQGPTPVCTPTF	?
Myc	P01106	T58	KKFELLPTPPLSPSR
NDRG1	Q92597	S342	TSLDGTRSRSHTSEG
NDRG1	Q92597	S352	HTSEGTRSRSHTSEG
NDRG1	Q92597	S362	HTSEGTRSRSHTSEG
Neurogenin 2	Q9H2A3	S234	SCTLSPASPGSDVDY
Neurogenin 2	Q9H2A3	S239	SPYSCTLSPASPAGS
PKAR2A	P13861	S48	REARAPASVLPAATP
Polycystin 2	Q13563	S76	AGAAASPSPPLSSCS
PPP1R2	P41236	T72	MKIDEPSTPYHSMIG
PXN	P49023	S126	SFPNKQKSAEPSPTV
Tau iso8	P10636-8	S262	NVKSKIGSTENLKHQ
Tau iso8	P10636-8	T231	KKVAVVRTPPKSPSS
TBX21	Q9UL17	S513	PSSGDSSSPAGAPSP	?

Protein Kinase Specificity

Matrix of observed frequency (%) of amino acids in aligned protein substrate phosphosites

Matrix Type:

Experimentally derived from alignment of 59 known protein substrate phosphosites and 11 peptides phosphorylated by recombinant GSK3-alpha in vitro tested in-house by Kinexus.

Domain #:

Inhibitors

For further details on these inhibitors click on the Compound Name and enter it into DrugKiNET or click on the ID's

Based on in vitro and/or in vivo phosphorylation data

Compound Name	KD, Ki or IC50 (nM)	PubChem ID	ChEMBL ID	PubMed ID

CHIR-98014	IC50 = 650 pM	9868037		12606497
CHEMBL1082152	Kd = 1.5 nM	11560568	1082152	20138512
CHEMBL362814	IC50 = 1.6 nM	11316975	362814	15686883
Alsterpaullone	IC50 = 4 nM	5005498	50894	15559249
GSK-3 Inhibitor IX	IC50 = 5 nM	5287844	409450	14761195
Kinome_3519	IC50 = 5 nM	16730109	259922	18359226
AC1O6ZUA	Kd < 10 nM	6539569	408019	19035792
CHIR 99021 (CT 99021)	IC50 = 10 nM	9956119	412142	12606497
GSK-3 Inhibitor X	IC50 = 10 nM	6538818	430226	14761195
CHEMBL1092754	IC50 = 10.6 nM	44541014	1092754	20188552
Staurosporine	IC50 = 12 nM	5279		16765046
AT7519	Kd = 23 nM	11338033		22037378
CHIR-124	IC50 = 23 nM	11502647		17255282
Kenpaullone	IC50 = 23 nM	3820	296586	18345612
GSK-3 Inhibitor XIII	Ki = 24 nM	6419766	359482	15715498
Alsterpaullone; 2-Cyanoethyl	IC50 < 25 nM	16760286	260138	22037377
AS601245	IC50 < 25 nM	11422035	191384	22037377
PKR Inhibitor	IC50 < 25 nM	6490494	235641	22037377
SB218078	IC50 < 25 nM	447446	289422	22037377
AC1NS7CD	Kd = 28 nM	5329665	295136	22037378
SNS032	Kd = 28 nM	3025986	296468	18183025
CHEMBL363607	IC50 = 31 nM	44398371	363607	15974571
SB216763	IC50 = 34 nM	176158
AG-E-60384	IC50 > 50 nM	6419741	413188	22037377
AR-A014418	IC50 > 50 nM	448014	259850	22037377
Bisindolylmaleimide I	IC50 > 50 nM	2396	7463	22037377
Gö6983	IC50 > 50 nM	3499	261491	22037377
GSK-3b Inhibitor XI	IC50 > 50 nM	10020713	272629	22037377
IDR E804	IC50 > 50 nM	6419764	1802727	22037377
JAK3 Inhibitor VI	IC50 > 50 nM	16760524		22037377
PKCb Inhibitor	IC50 > 50 nM	6419755	366266	22037377
Ro-32-0432	IC50 > 50 nM	127757	26501	22037377
SB415286	IC50 = 78 nM	4210951	322970	15559249
AT9283	IC50 > 100 nM	24905142		19143567
Cdk1/2 Inhibitor III	IC50 = 140 nM	5330812	261720	15974571
Bisindolylmaleimide IV	IC50 > 150 nM	2399	266487	22037377
Indirubin-3′-monoxime	IC50 > 150 nM	5326739		22037377
K-252a; Nocardiopsis sp.	IC50 > 150 nM	3813	281948	22037377
N-Benzoylstaurosporine	IC50 > 150 nM	56603681	608533	22037377
JNJ-7706621	Kd = 160 nM	5330790	191003	18183025
MK5108	IC50 = 169 nM	24748204		20053775
CHEMBL590109	IC50 = 170 nM	46224684	590109	19926477
AC1NS90Q	IC50 = 196 nM	5330392	372657	16033269
ALX-270-403-M001	IC50 > 250 nM			22037377
Gö6976	IC50 > 250 nM	3501	302449	22037377
GSK-3b Inhibitor II	IC50 > 250 nM	6539732	288064	22037377
TWS119	IC50 > 250 nM	9549289	405759	22037377
Alvocidib	IC50 = 280 nM	9910986	428690	15689157
R547	Kd = 280 nM	6918852		22037378
SU9516	IC50 = 350 nM	5289419	258805	15559249
Hesperadin	Kd < 400 nM	10142586	514409	19035792
LKB1(AAK1 dual inhibitor)	Kd < 400 nM	44588117	516312	19035792
Pyrimidylpyrrole, 11e	Ki = 400 nM	11634725	583042	19827834
Nintedanib	Kd = 430 nM	9809715	502835	22037378
Aloisine A	IC50 = 500 nM	5326843	75680	12519061
BMS-690514	Kd < 600 nM	11349170		21531814
AC1NS90N	IC50 = 606 nM	10187378	426587	16033269
CHEMBL248757	Ki = 911 nM	44444843	248757	17935989
Aloisine; RP106	IC50 = 920 nM	44350092	126343	12519061
A 443654	IC50 < 1 µM	10172943	379300	19465931
AZ960	IC50 = 1 µM	25099184		18775810
CP673451	IC50 > 1 µM	10158940		15705896
Kinome_714	IC50 > 1 µM	46886323		20346655
Silmitasertib	IC50 > 1 µM	24748573		21174434
SNS314	IC50 > 1 µM	16047143	514582	18678489
WZ3146	Kd > 1 µM	44607360		20033049
WZ4002	Kd > 1 µM	44607530		20033049
Apigenin	IC50 = 1.4 µM	5280443		15689157
Momelotinib	IC50 > 2 µM	25062766		19295546
NP12	IC50 = 2 µM	4124851	284861	16279768
Quercetin	IC50 = 2.1 µM	5280343	50	15689157
Lestaurtinib	Kd = 2.3 µM	126565		22037378
SureCN7685369	Kd < 2.5 µM	9925594	526901	19035792
CHEMBL387385	Ki = 3.3 µM	16115004	387385	17300186
A674563	Kd = 3.9 µM	11314340	379218	22037378
JNJ-28871063	IC50 > 4 µM	17747413		17975007

Disease Linkage

General Disease Association:

Cancer, neurological, and endocrine disorders

Specific Diseases (Non-cancerous):

Schizophrenia; Alzheimers disease (AD); Diabetes mellitus

Comments:

In Alzheimer’s Disease GSK3a is essential for maximal production of the aggregating proteins, amyloid-40 and -42.

Specific Cancer Types:

Sarcomas, Breast cancer

Comments:

GSK3 has been proposed as a tumour suppressor protein (TSP), since with loss of GSK3 there is an increase in WNT signalling, with a beta-catenin stabilization, leading to tumorigenesis. GSK3 has also been proposed to act as an oncoprotein (OP), as acute leukemia required GSK3 for cell proliferation. In most human cancers, it is up-regulated in expression about 1.6-times the rate observed for most protein kinases.

Gene Expression in Cancers:

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Cervical cancer (%CFC= +57, p<(0.0003); Ovary adenocarcinomas (%CFC= +88, p<0.0008); T-cell prolymphocytic leukemia (%CFC= +68, p<0.028); and Uterine leiomyosarcomas (%CFC= +52, p<0.021). The COSMIC website notes an up-regulated expression score for GSK3a in diverse human cancers of 725, which is 1.6-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 167 for this protein kinase in human cancers was 2.8-fold of the average score of 60 for the human protein kinases.

Mutagenesis Experiments:

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Mutation Rate in All Cancers:

Percent mutation rates per 100 amino acids length in human cancers: 0.06 % in 25371 diverse cancer specimens. This rate is only -16 % lower than the average rate of 0.075 % calculated for human protein kinases in general.

Mutation Rate in Specific Cancers:

Highest percent mutation rates per 100 amino acids length in human cancers: 0.41 % in 1270 large intestine cancers tested; 0.34 % in 603 endometrium cancers tested; 0.21 % in 589 stomach cancers tested; 0.15 % in 548 urinary tract cancers tested; 0.07 % in 864 skin cancers tested; 0.07 % in 1512 liver cancers tested; 0.06 % in 1276 kidney cancers tested; 0.05 % in 1956 lung cancers tested.

Frequency of Mutated Sites:

None > 5 in 20,654 cancer specimens

Comments:

Only 1 deletion, and no insertions or complex mutations are noted on the COSMIC website.

COSMIC Entry:

GSK3a

OMIM Entry:

606784

Nomenclature

Short Name:

Full Name:

Alias:

Classification

Type:

Group:

Family:

SubFamily:

Specific Links

General Links

Structure

Mol. Mass (Da):

# Amino Acids:

# mRNA Isoforms:

mRNA Isoforms:

4D Structure:

3D Structure:

1D Structure:

Subfamily Alignment

Domain Distribution:

Kinexus Products

hiddentext

Post-translation Modifications

Serine phosphorylated:

Threonine phosphorylated:

Tyrosine phosphorylated:

Ubiquitinated:

Distribution

Human Tissue Distribution

% Max Expression: Mean Expression: Number of Samples: Standard Deviation:

% Max Expression: Mean Expression: Number of Samples: Standard Deviation:

Evolution

Species Conservation

PhosphoNET % Identity: PhosphoNET % Similarity: Homologene %Identity:

PhosphoNET % Identity: PhosphoNET % Similarity: Homologene %Identity:

Regulation

Activation:

Inhibition:

Synthesis:

Degradation:

Known Upstream Kinases

Based on in vitro and/or in vivo phosphorylation data

Known Downstream Substrates

Based on in vitro and/or in vivo phosphorylation data

Protein Kinase Specificity

Matrix Type:

Domain #:

Inhibitors

Based on in vitro and/or in vivo phosphorylation data

Disease Linkage

General Disease Association:

Specific Diseases (Non-cancerous):

Comments:

Specific Cancer Types:

Comments:

Gene Expression in Cancers:

Mutagenesis Experiments:

Mutation Rate in All Cancers:

Mutation Rate in Specific Cancers:

Frequency of Mutated Sites:

Comments:

COSMIC Entry:

OMIM Entry:

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:

PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity: