KinaseNET

Nomenclature

Short Name:

MARK2

Full Name:

Serine-threonine-protein kinase MARK2

Alias:

EC 2.7.11.1
ELKL motif kinase 1
MAP/microtubule affinity-regulating kinase 2
PAR-1
Par1b
PAR-1b
EMK
EMK1
Kinase MARK2
MGC99619

Classification

Type:

Protein-serine/threonine kinase

Group:

CAMK

Family:

CAMKL

SubFamily:

MARK

Specific Links

Entrez-Gene Entry:	2011
Entrez-Protein Entry:	NP_059672
GeneCards Entry:	EMK1
KinBASE Entry:	MARK2
OMIM Entry:	600526
Pfam Entry:	Q7KZI7
PhosphoNET Entry:	Q7KZI7
Phosphosite Plus Entry:	2099
Protein Data Bank Entry:	1Y8G
Source Entry:	MARK2
UniProt Entry:	Q7KZI7
Kinexus Products:	MARK2 MAP/microtubule affinity-regulating protein-serine kinase 2 pan-specific antibody AB-NK275-1 MAP/microtubule affinity-regulating protein-serine kinase 2 pan-specific antibody AB-NK275-2 Cdc25C (205-225), KinSub - Cdc25C phosphatase (V205-R225, human) peptide; Chktide peptide - Powder PE-01ACN95 MAP/microtubule affinity-regulating protein-serine kinase 2 (P19-G37, human) peptide - Powder PE-01BDR80 MAP/microtubule affinity-regulating protein-serine kinase 2 (G676-P690, human) peptide - Powder PE-01BDS80

General Links

Structure

Mol. Mass (Da):

87,911

# Amino Acids:

788

# mRNA Isoforms:

mRNA Isoforms:

87,911 Da (788 AA; Q7KZI7); 86,762 Da (779 AA; Q7KZI7-8); 86,129 Da (773 AA; Q7KZI7-11); 84,333 Da (755 AA; Q7KZI7-6); 83,184 Da (746 AA; Q7KZI7-3); 83,113 Da (745 AA; Q7KZI7-14); 82,551 Da (740 AA; Q7KZI7-12); 82,429 Da (734 AA; Q7KZI7-9); 81,280 Da (725 AA; Q7KZI7-4); 81,209 Da (724 AA; Q7KZI7-16); 80,647 Da (719 AA; Q7KZI7-5); 79,427 Da (709 AA; Q7KZI7-15); 78,851 Da (701 AA; Q7KZI7-2); 77,702 Da (692 AA; Q7KZI7-7); 77,631 Da (691 AA; Q7KZI7-13); 77,069 Da (686 AA; Q7KZI7-10)

4D Structure:

1D Structure:

Retrieve Gene Sequence
Retrieve Full Protein Sequence
Retrieve Catalytic Domain Sequence

Subfamily Alignment

Domain Distribution:

Start	End	Domain
53	304	Pkinase
323	362	UBA
739	788	KA1

Kinexus Products

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

hiddentext

○	MAP/microtubule affinity-regulating protein-serine kinase 2 pan-specific antibody AB-NK275-1
○	MAP/microtubule affinity-regulating protein-serine kinase 2 pan-specific antibody AB-NK275-2
○	Cdc25C (205-225), KinSub - Cdc25C phosphatase (V205-R225, human) peptide; Chktide peptide - Powder PE-01ACN95
○	MAP/microtubule affinity-regulating protein-serine kinase 2 (P19-G37, human) peptide - Powder PE-01BDR80
○	MAP/microtubule affinity-regulating protein-serine kinase 2 (G676-P690, human) peptide - Powder PE-01BDS80

Post-translation Modifications

For detailed information on phosphorylation of this kinase go to PhosphoNET

Serine phosphorylated:

S26, S29, S30, S40, S43, S197, S212-, S290, S365, S380, S386, S390, S400, S409, S422, S449, S456, S471, S477, S479, S483, S486, S493, S498, S533, S535, S569, S571, S576, S578, S592, S593, S595, S619, S621, S624, S631, S633, S648, S675, S692, S698, S722, S759.

Threonine phosphorylated:

T6, T20, T42, T58, T87, T201, T208+, T329, T338, T450, T466, T467, T469, T472, T596-, T616, T667.

Tyrosine phosphorylated:

Y323, Y337, Y351, Y358, Y363, Y613.

Ubiquitinated:

K637.

Distribution

Based on gene microarray analysis from the NCBI

Human Tissue Distribution

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

100

933

32

1622
6

53

14

49
26

241

35

290
30

276

117

406
65

607

22

499
2

18

74

16
34

313

35

476
38

354

65

433
37

348

17

256
9

88

118

128
12

114

60

150
46

429

219

500
15

142

57

184
5

48

12

35
23

211

52

253
4

33

14

20
7

64

226

160
30

280

44

297
8

73

116

159
43

402

109

480
19

175

50

182
21

198

56

239
30

277

45

484
19

181

42

198
22

204

50

243
47

441

75

466
35

323

60

668
45

417

42

1258
19

180

44

195
9

83

28

119
63

592

36

424
80

742

36

789
6

59

102

178
62

581

57

533
19

174

53

303

Evolution

Species Conservation

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

100

100

100
68.2

80.4

100
99.8

99.8

100
-

-

98
-

-

99
95.1

96.2

98
-

-

-
96.7

97.7

98
90

91

97
-

-

-
68.5

80.6

-
30.3

48.8

-
84.4

91.8

85
27.6

42.7

77
-

-

-
-

-

-
-

-

-
38.8

49.9

-
-

-

-
-

-

-
-

-

-
-

-

-
26.5

44.2

-
27.5

45.6

-
-

-

-

For a wider analysis go to PhosphoNET Evolution in PhosphoNET

Binding Proteins

Examples of known interacting proteins

hiddentext

No.	Name – UniProt ID
1	YWHAZ - P63104
2	STK11 - Q15831
3	DVL3 - Q92997
4	YWHAB - P31946
5	GSK3B - P49841
6	NUAK1 - O60285
7	YWHAE - P62258
8	PARD6A - Q9NPB6
9	YWHAH - Q04917
10	YWHAQ - P27348

Regulation

Activation:

Activated by phosphorylation on Thr-208 by STK11 in complex with STE20-related adapter-alpha (STRAD alpha) pseudo kinase and CAB39.

Inhibition:

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

LKB1	Q15831	T208	TFGNKLDTFCGSPPY	+
TAO1	Q7L7X3	T208	TFGNKLDTFCGSPPY	+
GSK3B	P49841	S212	KLDTFCGSPPYAAPE	-
MARK2	Q7KZI7	S400	HKVQRSVSANPKQRR	?
PKD1	Q15139	S400	HKVQRSVSANPKQRR	?
PKD2	Q9BZL6	S400	HKVQRSVSANPKQRR	?
ERK1	P27361	S456	STAKVPASPLPGLER
PKCi	P41743	T596	RGVSSRSTFHAGQLR	-
PKCz	Q05513	T596	RGVSSRSTFHAGQLR	-
ERK1	P27361	S619	PYGVTPASPSGHSQG

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

HDAC4	P56524	S246	FPLRKTASEPNLKLR
HDAC5	Q9UQL6	S259	FPLRKTASEPNLKVR
HDAC7	Q8WUI4	S155	FPLRKTVSEPNLKLR	-
MARK2	Q7KZI7	S400	HKVQRSVSANPKQRR	?
Rab11FIP2	Q7L804	S227	QRLSSAHSMSDLSGS	?
Tau iso8	P10636-8	S262	NVKSKIGSTENLKHQ
Tau iso8	P10636-8	S293	NVQSKCGSKDNIKHV
Tau iso8	P10636-8	S324	KVTSKCGSLGNIHHK
Tau iso8	P10636-8	S356	RVQSKIGSLDNITHV
TORC2 (CRTC2)	Q53ET0	S274	PAMNTGGSLPDLTNL

Protein Kinase Specificity

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

Matrix Type:

Predicted from the application of the Kinexus Kinase Substrate Predictor Version 2.0 algorithm, which was trained with over 10,000 kinase-protein substrate pairs and 8,000 kinase-peptide substrate pairs.

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

Staurosporine	Kd = 100 pM	5279		15711537
TTT-3002	IC50 < 4 nM
Lestaurtinib	Kd = 14 nM	126565		22037378
Cdk1/2 Inhibitor III	IC50 < 25 nM	5330812	261720	22037377
JAK3 Inhibitor VI	IC50 < 25 nM	16760524		22037377
K-252a; Nocardiopsis sp.	IC50 < 25 nM	3813	281948	22037377
BX795	IC50 < 40 nM	10077147	577784
NVP-TAE684	Kd = 44 nM	16038120	509032	22037378
Gö6976	IC50 > 50 nM	3501	302449	22037377
SB218078	IC50 > 50 nM	447446	289422	22037377
SU11652	IC50 > 50 nM	24906267	13485	22037377
MRT67307	IC50 < 60 nM	44464263
AT9283	IC50 > 100 nM	24905142		19143567
N-Benzoylstaurosporine	Kd = 100 nM	56603681	608533	18183025
Hesperadin	Kd < 150 nM	10142586	514409	19035792
PKR Inhibitor	IC50 > 150 nM	6490494	235641	22037377
AG-E-60384	IC50 > 250 nM	6419741	413188	22037377
ALX-270-403-M001	IC50 > 250 nM			22037377
BCP9000906	IC50 > 250 nM	5494425	21156	22037377
SU11274	IC50 > 250 nM	9549297	261641	22037377
Sunitinib	Kd = 310 nM	5329102	535	18183025
CHEMBL1240703	Kd = 400 nM	52945601	1240703	19654408
KW2449	Kd = 440 nM	11427553	1908397	22037378
SU14813	Kd = 440 nM	10138259	1721885	18183025
Alsterpaullone	IC50 = 500 nM	5005498	50894	22037377
BML-275	IC50 = 500 nM	11524144	478629	22037377
Dovitinib	IC50 = 500 nM	57336746		22037377
SU9516	IC50 = 500 nM	5289419	258805	22037377
Syk Inhibitor	IC50 = 500 nM	6419747	104279	22037377
Amgen TBK 1 inhibitor (Compound II)	IC50 < 600 nM
Staurosporine aglycone	IC50 < 600 nM	3035817	281948
Ruxolitinib	Kd = 660 nM	25126798	1789941	22037378
GSK690693	Kd = 720 nM	16725726	494089	22037378
IKK-3 inhibitor IX	IC50 < 800 nM	11626927	373751
SU6656	IC50 < 800 nM	5353978	605003
GSK-3 Inhibitor IX	IC50 > 900 nM	5287844	409450
GSK650394A	IC50 > 900 nM	25022668	558642
A 443654	IC50 < 1 µM	10172943	379300	19465931
Alsterpaullone; 2-Cyanoethyl	IC50 > 1 µM	16760286	260138	22037377
Aurora A Inhibitor 1 (DF)	Kd = 1 µM			21992004
BI-D1870	IC50 = 1 µM	25023738	573107
Febuxostat	IC50 = 1 µM	134018	1164729
Flt-3 Inhibitor II	IC50 > 1 µM	11601743	377193	22037377
IDR E804	IC50 > 1 µM	6419764	1802727	22037377
MK5108	IC50 > 1 µM	24748204		20053775
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
JNJ-7706621	Kd = 1.2 µM	5330790	191003	18183025
Nintedanib	Kd = 1.4 µM	9809715	502835	22037378
Tozasertib	Kd = 1.4 µM	5494449	572878	18183025
1;9-Pyrazoloanthrone	Kd = 1.8 µM	8515	7064	15711537
Ruboxistaurin	Kd = 2.3 µM	153999	91829	15711537
AC1NS4N8	Kd < 2.5 µM	5353854	101797	19035792
LKB1(AAK1 dual inhibitor)	Kd < 2.5 µM	44588117	516312	19035792
SureCN5302803	Kd > 2.5 µM	24788740		19035792
HG-9-91-01	IC50 > 3 µM
R406	IC50 > 3 µM	11984591
TG101348	Kd = 3.1 µM	16722836	1287853	22037378
SureCN4875304	IC50 > 3.5 µM	46871765		20472445
PHA-665752	Kd = 3.6 µM	10461815	450786	22037378
JNJ-28871063	IC50 > 4 µM	17747413		17975007
Ro-31-8220	IC50 < 4 µM	5083	6291
CHEMBL248757	Ki = 4.266 µM	44444843	248757	17935989
BI-78D3	IC50 > 4.5 µM	2747117	508280
GDC-0941	IC50 > 4.5 µM	17755052	521851
PP242	IC50 > 4.5 µM	25243800
Wyeth PDK1 Inhibitor Compound 1	IC50 > 4.5 µM

Disease Linkage

General Disease Association:

Neurological disorders

Specific Diseases (Non-cancerous):

Alzheimer's disease (AD)

Comments:

Alzheimer’s disease had a positive correlation with increased Mark2-tau complexes, leading to increased tau phosphorylation (on S262).

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 human Bladder carcinomas (%CFC= +45, p<0.003). The COSMIC website notes an up-regulated expression score for MARK2 in diverse human cancers of 464, which is close to the average score of 462 for the human protein kinases. The down-regulated expression score of 136 for this protein kinase in human cancers was 2.3-fold of the average score of 60 for the human protein kinases.

Mutagenesis Experiments:

Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis. The phosphorylation of MARK2 by the LKB can occur with a T208A mutation in MARK2. The ability of MARK2 to bind the 14-3-3 protein YWHAZ and to dissociate from the membrane can also stil occur with a T596A mutation.

Mutation Rate in All Cancers:

Percent mutation rates per 100 amino acids length in human cancers: 0.08 % in 25158 diverse cancer specimens. This rate is very similar (+ 5% higher) to 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: 0.32 % in 1270 large intestine cancers tested; 0.28 % in 864 skin cancers tested; 0.28 % in 589 stomach cancers tested; 0.21 % in 548 urinary tract cancers tested; 0.14 % in 273 cervix cancers tested; 0.14 % in 1634 lung cancers tested; 0.11 % in 710 oesophagus cancers tested; 0.11 % in 603 endometrium cancers tested; 0.09 % in 1512 liver cancers tested; 0.08 % in 939 prostate cancers tested; 0.07 % in 1467 pancreas cancers tested; 0.05 % in 1490 breast cancers tested; 0.05 % in 1276 kidney cancers tested; 0.04 % in 2082 central nervous system cancers tested; 0.03 % in 891 ovary cancers tested; 0.03 % in 441 autonomic ganglia cancers tested; 0.02 % in 558 thyroid cancers tested; 0.01 % in 942 upper aerodigestive tract cancers tested; 0.01 % in 2009 haematopoietic and lymphoid cancers tested.

Frequency of Mutated Sites:

None > 3 in 20,441 cancer specimens

Comments:

Only 6 deletions, 2 insertions and no complex mutations are noted on the COSMIC website.

COSMIC Entry:

MARK2

OMIM Entry:

600526

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:

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:

Binding Proteins

hiddentext

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:

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: