dbPTM

MP2K4_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	MP2K4_HUMAN
UniProt AC	P45985
Protein Name	Dual specificity mitogen-activated protein kinase kinase 4
Gene Name	MAP2K4
Organism	Homo sapiens (Human).
Sequence Length	399
Subcellular Localization	Cytoplasm. Nucleus.
Protein Description	Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14..
Protein Sequence	MAAPSPSGGGGSGGGSGSGTPGPVGSPAPGHPAVSSMQGKRKALKLNFANPPFKSTARFTLNPNPTGVQNPHIERLRTHSIESSGKLKISPEQHWDFTAEDLKDLGEIGRGAYGSVNKMVHKPSGQIMAVKRIRSTVDEKEQKQLLMDLDVVMRSSDCPYIVQFYGALFREGDCWICMELMSTSFDKFYKYVYSVLDDVIPEEILGKITLATVKALNHLKENLKIIHRDIKPSNILLDRSGNIKLCDFGISGQLVDSIAKTRDAGCRPYMAPERIDPSASRQGYDVRSDVWSLGITLYELATGRFPYPKWNSVFDQLTQVVKGDPPQLSNSEEREFSPSFINFVNLCLTKDESKRPKYKELLKHPFILMYEERAVEVACYVCKILDQMPATPSSPMYVD

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
2	Acetylation	------MAAPSPSGG ------CCCCCCCCC	28.25	19413330
5	Phosphorylation	---MAAPSPSGGGGS ---CCCCCCCCCCCC	27.29	26055452
7	Phosphorylation	-MAAPSPSGGGGSGG -CCCCCCCCCCCCCC	55.17	29116813
7	O-linked_Glycosylation	-MAAPSPSGGGGSGG -CCCCCCCCCCCCCC	55.17	29351928
12	Phosphorylation	SPSGGGGSGGGSGSG CCCCCCCCCCCCCCC	37.22	22199227
16	Phosphorylation	GGGSGGGSGSGTPGP CCCCCCCCCCCCCCC	32.82	25850435
18	Phosphorylation	GSGGGSGSGTPGPVG CCCCCCCCCCCCCCC	40.99	22199227
20	Phosphorylation	GGGSGSGTPGPVGSP CCCCCCCCCCCCCCC	27.11	22199227
22	Ubiquitination	GSGSGTPGPVGSPAP CCCCCCCCCCCCCCC	29.39	22817900
25	Ubiquitination	SGTPGPVGSPAPGHP CCCCCCCCCCCCCCC	30.92	22817900
26	Phosphorylation	GTPGPVGSPAPGHPA CCCCCCCCCCCCCCC	20.37	25159151
35	Phosphorylation	APGHPAVSSMQGKRK CCCCCCCHHHCCCHH	23.38	22199227
36	O-linked_Glycosylation	PGHPAVSSMQGKRKA CCCCCCHHHCCCHHH	14.44	29351928
36	Phosphorylation	PGHPAVSSMQGKRKA CCCCCCHHHCCCHHH	14.44	20068231
42	Methylation	SSMQGKRKALKLNFA HHHCCCHHHHHCCCC	62.65	115973059
45	Methylation	QGKRKALKLNFANPP CCCHHHHHCCCCCCC	46.36	100288009
54	Ubiquitination	NFANPPFKSTARFTL CCCCCCCCCCEEEEE	53.31	32015554
54	Methylation	NFANPPFKSTARFTL CCCCCCCCCCEEEEE	53.31	54395153
56	Phosphorylation	ANPPFKSTARFTLNP CCCCCCCCEEEEECC	23.57	-
58	Asymmetric dimethylarginine	PPFKSTARFTLNPNP CCCCCCEEEEECCCC	25.77	-
58	Methylation	PPFKSTARFTLNPNP CCCCCCEEEEECCCC	25.77	24129315
60	Phosphorylation	FKSTARFTLNPNPTG CCCCEEEEECCCCCC	21.77	28555341
65	Ubiquitination	RFTLNPNPTGVQNPH EEEECCCCCCCCCCC	31.61	32015554
66	O-linked_Glycosylation	FTLNPNPTGVQNPHI EEECCCCCCCCCCCH	57.53	OGP
78	Phosphorylation	PHIERLRTHSIESSG CCHHHHHCCEECCCC	25.27	23403867
80	Phosphorylation	IERLRTHSIESSGKL HHHHHCCEECCCCCC	27.69	27273156
83	Phosphorylation	LRTHSIESSGKLKIS HHCCEECCCCCCCCC	42.60	23403867
84	Phosphorylation	RTHSIESSGKLKISP HCCEECCCCCCCCCH	27.44	23403867
85	Ubiquitination	THSIESSGKLKISPE CCEECCCCCCCCCHH	48.90	24816145
86	Ubiquitination	HSIESSGKLKISPEQ CEECCCCCCCCCHHH	48.86	29967540
88	Ubiquitination	IESSGKLKISPEQHW ECCCCCCCCCHHHHC	44.62	29967540
90	Phosphorylation	SSGKLKISPEQHWDF CCCCCCCCHHHHCCC	22.31	25159151
97	Ubiquitination	SPEQHWDFTAEDLKD CHHHHCCCCHHHHHH	6.18	29967540
98	Phosphorylation	PEQHWDFTAEDLKDL HHHHCCCCHHHHHHH	27.02	28464451
99	Ubiquitination	EQHWDFTAEDLKDLG HHHCCCCHHHHHHHH	14.32	29967540
101	Phosphorylation	HWDFTAEDLKDLGEI HCCCCHHHHHHHHHH	57.46	32645325
103	Ubiquitination	DFTAEDLKDLGEIGR CCCHHHHHHHHHHCC	64.33	29967540
113	Ubiquitination	GEIGRGAYGSVNKMV HHHCCCCCCCHHHCC	16.86	24816145
114	Ubiquitination	EIGRGAYGSVNKMVH HHCCCCCCCHHHCCC	25.28	29967540
131	Acetylation	SGQIMAVKRIRSTVD CCCEEEEEEHHHCCC	32.35	19608861
131	Ubiquitination	SGQIMAVKRIRSTVD CCCEEEEEEHHHCCC	32.35	19608861
140	Ubiquitination	IRSTVDEKEQKQLLM HHHCCCHHHHHHHHH	62.07	22817900
142	Ubiquitination	STVDEKEQKQLLMDL HCCCHHHHHHHHHHH	50.27	29967540
142	Acetylation	STVDEKEQKQLLMDL HCCCHHHHHHHHHHH	50.27	19608861
143	Ubiquitination	TVDEKEQKQLLMDLD CCCHHHHHHHHHHHH	43.96	1973793
151	Ubiquitination	QLLMDLDVVMRSSDC HHHHHHHHHHHCCCC	4.78	22817900
154	Ubiquitination	MDLDVVMRSSDCPYI HHHHHHHHCCCCCHH	22.77	22817900
214	Ubiquitination	KITLATVKALNHLKE HHHHHHHHHHHHHHH	42.68	29967540
220	Ubiquitination	VKALNHLKENLKIIH HHHHHHHHHHHEEEC	36.69	32015554
225	Ubiquitination	HLKENLKIIHRDIKP HHHHHHEEECCCCCH	3.46	29967540
231	Ubiquitination	KIIHRDIKPSNILLD EEECCCCCHHHEEEC	46.84	32015554
242	Ubiquitination	ILLDRSGNIKLCDFG EEECCCCCEEECCCC	29.48	24816145
251	Phosphorylation	KLCDFGISGQLVDSI EECCCCCCHHHHHHH	22.36	30108239
257	Phosphorylation	ISGQLVDSIAKTRDA CCHHHHHHHHHHCCC	19.57	22322096
261	Phosphorylation	LVDSIAKTRDAGCRP HHHHHHHHCCCCCCC	25.43	22322096
269	Phosphorylation	RDAGCRPYMAPERID CCCCCCCCCCCCCCC	6.12	24719451
278	Phosphorylation	APERIDPSASRQGYD CCCCCCCCHHHCCCC	34.82	24719451
288	Phosphorylation	RQGYDVRSDVWSLGI HCCCCCHHHHHHHCC	36.04	21406692
292	Phosphorylation	DVRSDVWSLGITLYE CCHHHHHHHCCCHHH	19.30	21406692
296	Phosphorylation	DVWSLGITLYELATG HHHHHCCCHHHHHHC	22.84	21406692
298	Phosphorylation	WSLGITLYELATGRF HHHCCCHHHHHHCCC	10.55	21406692
302	Phosphorylation	ITLYELATGRFPYPK CCHHHHHHCCCCCCC	41.33	21406692
312	Phosphorylation	FPYPKWNSVFDQLTQ CCCCCHHHHHHHHHH	24.05	28857561
391	Phosphorylation	ILDQMPATPSSPMYV HHHCCCCCCCCCCCC	20.17	27273156
393	Phosphorylation	DQMPATPSSPMYVD- HCCCCCCCCCCCCC-	42.60	30278072
394	Phosphorylation	QMPATPSSPMYVD-- CCCCCCCCCCCCC--	18.19	27273156
397	Phosphorylation	ATPSSPMYVD----- CCCCCCCCCC-----	12.59	23403867
402	Phosphorylation	PMYVD---------- CCCCC----------		32142685
405	Phosphorylation	VD------------- CC-------------		32142685

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
80	S	Phosphorylation	Kinase	PKB_GROUP	-	PhosphoELM
80	S	Phosphorylation	Kinase	AKT-FAMILY	-	GPS
80	S	Phosphorylation	Kinase	SGK1	O00141	PSP
80	S	Phosphorylation	Kinase	AKT1	P31749	PSP
257	S	Phosphorylation	Kinase	MAP2K4	P45985	GPS
257	S	Phosphorylation	Kinase	MAP3K	-	Uniprot
257	S	Phosphorylation	Kinase	MAP3K-FAMILY	-	GPS
257	S	Phosphorylation	Kinase	MAP3K3	Q99759	GPS
257	S	Phosphorylation	Kinase	MAP3K2	Q9Y2U5	GPS
257	S	Phosphorylation	Kinase	MAP3K11	Q16584	GPS
261	T	Phosphorylation	Kinase	MAP3K5	Q99683	GPS
261	T	Phosphorylation	Kinase	MAP3K3	Q99759	GPS
261	T	Phosphorylation	Kinase	MAP2K4	P45985	GPS
261	T	Phosphorylation	Kinase	MAP3K2	Q9Y2U5	GPS
261	T	Phosphorylation	Kinase	MAP3K-FAMILY	-	GPS
261	T	Phosphorylation	Kinase	MAP3K11	Q16584	GPS
261	T	Phosphorylation	Kinase	MAP3K	-	Uniprot
-	K	Ubiquitination	E3 ubiquitin ligase	ITCH	Q96J02	PMID:19737936

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
257	S	Phosphorylation	19369195
Activated by phosphorylation on Ser-257 and Thr-261 by MAP kinase kinase kinases (MAP3Ks).
261	T	Phosphorylation	9003778
Activated by phosphorylation on Ser-257 and Thr-261 by MAP kinase kinase kinases (MAP3Ks).

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Modified Location	Modification	Variant Position (Distance <= 10)	Residue Change	SAP	Related Disease	Reference
Oops, there are no SNP-PTM records of MP2K4_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
FLNC_HUMAN	FLNC	physical	9006895
FLNA_MOUSE	Flna	physical	9006895
MK08_HUMAN	MAPK8	physical	12391307
MP2K7_HUMAN	MAP2K7	genetic	11062067
AKT1_HUMAN	AKT1	physical	11707464
MK08_HUMAN	MAPK8	physical	11707464
MK08_HUMAN	MAPK8	physical	11279118
MK08_HUMAN	MAPK8	physical	10713157
ITCH_HUMAN	ITCH	physical	19737936
MK09_HUMAN	MAPK9	physical	21900206
PML_HUMAN	PML	physical	10620019
MK10_HUMAN	MAPK10	physical	15299005
M3K1_HUMAN	MAP3K1	physical	15299005
M3K5_HUMAN	MAP3K5	physical	15299005
M3K1_HUMAN	MAP3K1	physical	15866172
M3K4_HUMAN	MAP3K4	physical	15866172
M3K1_HUMAN	MAP3K1	physical	9808624
MK08_HUMAN	MAPK8	physical	9162092
MP2K4_HUMAN	MAP2K4	physical	9162092
MK14_HUMAN	MAPK14	physical	9162092
MK08_HUMAN	MAPK8	physical	9808624
MK14_HUMAN	MAPK14	physical	9808624
AKT1_HUMAN	AKT1	physical	15998799
MK08_HUMAN	MAPK8	physical	15998799
A4_HUMAN	APP	physical	21832049
MK08_HUMAN	MAPK8	physical	13130464
MP2K7_HUMAN	MAP2K7	physical	13130464
JUN_HUMAN	JUN	physical	13130464
M3K7_HUMAN	MAP3K7	physical	12556533
MK10_HUMAN	MAPK10	physical	12788955
MK08_HUMAN	MAPK8	physical	12788955
MK09_HUMAN	MAPK9	physical	12788955
MK01_HUMAN	MAPK1	physical	12788955
GEMI5_HUMAN	GEMIN5	physical	17541429
CTIP_HUMAN	RBBP8	physical	21988832
NBR1_HUMAN	NBR1	physical	25043814
M3K3_HUMAN	MAP3K3	physical	25043814
KTI12_HUMAN	KTI12	physical	26344197
VASP_HUMAN	VASP	physical	26344197
FLNB_HUMAN	FLNB	physical	19270716

Drug and Disease Associations

Kegg Disease
There are no disease associations of PTM sites.
OMIM Disease
There are no disease associations of PTM sites.
Kegg Drug
There are no disease associations of PTM sites.
DrugBank
There are no disease associations of PTM sites.

Regulatory Network of MP2K4_HUMAN

Related Literatures of Post-Translational Modification

Acetylation
Reference	PubMed
"Lys-N and trypsin cover complementary parts of the phosphoproteome ina refined SCX-based approach."; Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,Mohammed S.; Anal. Chem. 81:4493-4501(2009). Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGESCALE ANALYSIS] AT SER-18; SER-26 AND SER-394, AND MASS SPECTROMETRY.	19413330 [Abstract]
Phosphorylation
Reference	PubMed
"Large-scale proteomics analysis of the human kinome."; Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,Mann M., Daub H.; Mol. Cell. Proteomics 8:1751-1764(2009). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-80; SER-257; THR-391 ANDSER-394, AND MASS SPECTROMETRY.	19369195 [Abstract]
"Lys-N and trypsin cover complementary parts of the phosphoproteome ina refined SCX-based approach."; Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,Mohammed S.; Anal. Chem. 81:4493-4501(2009). Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGESCALE ANALYSIS] AT SER-18; SER-26 AND SER-394, AND MASS SPECTROMETRY.	19413330 [Abstract]
"A quantitative atlas of mitotic phosphorylation."; Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,Elledge S.J., Gygi S.P.; Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-90, AND MASSSPECTROMETRY.	18669648 [Abstract]

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