MK11_HUMAN - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: MK11_HUMAN
• UniProt AC: Q15759
• Protein Name: Mitogen-activated protein kinase 11
• Gene Name: MAPK11
• Organism: Homo sapiens (Human).
• Sequence Length: 364
• Subcellular Localization: Cytoplasm. Nucleus.
• Protein Description: Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK11 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK11 functions are mostly redundant with those of MAPK14. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Additional examples of p38 MAPK substrates are the FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment..
• Protein Sequence: MSGPRAGFYRQELNKTVWEVPQRLQGLRPVGSGAYGSVCSAYDARLRQKVAVKKLSRPFQSLIHARRTYRELRLLKHLKHENVIGLLDVFTPATSIEDFSEVYLVTTLMGADLNNIVKCQALSDEHVQFLVYQLLRGLKYIHSAGIIHRDLKPSNVAVNEDCELRILDFGLARQADEEMTGYVATRWYRAPEIMLNWMHYNQTVDIWSVGCIMAELLQGKALFPGSDYIDQLKRIMEVVGTPSPEVLAKISSEHARTYIQSLPPMPQKDLSSIFRGANPLAIDLLGRMLVLDSDQRVSAAEALAHAYFSQYHDPEDEPEAEPYDESVEAKERTLEEWKELTYQEVLSFKPPEPPKPPGSLEIEQ

Overview of Protein Modification Sites with Functional and Structural Information

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
53	Ubiquitination	LRQKVAVKKLSRPFQ HHHHHHHHHHCCHHH	37.95	24816145
61	Phosphorylation	KLSRPFQSLIHARRT HHCCHHHHHHHHHHH	29.66	30243723
68	Phosphorylation	SLIHARRTYRELRLL HHHHHHHHHHHHHHH	22.75	30243723
69	Phosphorylation	LIHARRTYRELRLLK HHHHHHHHHHHHHHH	10.57	30243723
143	Phosphorylation	RGLKYIHSAGIIHRD HHHHHHHHCCCCCCC	20.73	-
180	Phosphorylation	RQADEEMTGYVATRW CCCCHHHHHHHHHCC	28.74	21082442
182	Phosphorylation	ADEEMTGYVATRWYR CCHHHHHHHHHCCEE	4.26	20007894
185	Phosphorylation	EMTGYVATRWYRAPE HHHHHHHHCCEECHH	16.22	28152594
241	Phosphorylation	RIMEVVGTPSPEVLA HHHHHHCCCCHHHHH	14.69	-
243	Phosphorylation	MEVVGTPSPEVLAKI HHHHCCCCHHHHHHH	33.27	19664994
251	Phosphorylation	PEVLAKISSEHARTY HHHHHHHCHHHHHHH	29.03	19664994
261	Phosphorylation	HARTYIQSLPPMPQK HHHHHHHHCCCCCHH	33.03	-
268	Acetylation	SLPPMPQKDLSSIFR HCCCCCHHHHHHHHC	55.56	25953088
271	Phosphorylation	PMPQKDLSSIFRGAN CCCHHHHHHHHCCCC	31.36	28188228
272	Phosphorylation	MPQKDLSSIFRGANP CCHHHHHHHHCCCCH	32.80	27794612
323	Phosphorylation	DEPEAEPYDESVEAK CCCCCCCCCHHHHHH	24.69	-
347	Phosphorylation	LTYQEVLSFKPPEPP CCHHHHHCCCCCCCC	36.08	24719451
359	Phosphorylation	EPPKPPGSLEIEQ-- CCCCCCCCCCCCC--	28.71	-

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
180	T	Phosphorylation	Kinase	MAP2K3	P46734	Uniprot
180	T	Phosphorylation	Kinase	MAP2K4	P45985	Uniprot
180	T	Phosphorylation	Kinase	MAP2K6	P52564	Uniprot
182	Y	Phosphorylation	Kinase	MAP2K3	P46734	Uniprot
182	Y	Phosphorylation	Kinase	MAP2K4	P45985	Uniprot
182	Y	Phosphorylation	Kinase	MAP2K6	P52564	Uniprot
182	Y	Phosphorylation	Kinase	RET	P07949	GPS
241	T	Phosphorylation	Kinase	MAPK11	Q15759	GPS
261	S	Phosphorylation	Kinase	MAPK11	Q15759	GPS
323	Y	Phosphorylation	Kinase	ZAP70	P43403	Uniprot
-	K	Ubiquitination	E3 ubiquitin ligase	TANK	Q92844	PMID:22199232

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
180	T	Phosphorylation	Dually phosphorylated on Thr-180 and Tyr-182 by MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6, which activates the enzyme.	15356147

Disease-associated PTM Sites based on SAP

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

Oops, there are no SNP-PTM records of MK11_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
HDAC3_HUMAN	HDAC3	physical	15356147
PML_HUMAN	PML	physical	15273249
CCND1_HUMAN	CCND1	physical	10952989
RPC4_HUMAN	POLR3D	physical	21900206
TLS1_HUMAN	C9orf78	physical	21900206
CPNE6_HUMAN	CPNE6	physical	21900206
MK14_HUMAN	MAPK14	physical	21900206
SOCS3_HUMAN	SOCS3	physical	21900206
MBP_HUMAN	MBP	physical	17906618
HTRA2_HUMAN	HTRA2	physical	17906618
A4_HUMAN	APP	physical	21832049
ATF2_HUMAN	ATF2	physical	9235954
SH21A_HUMAN	SH2D1A	physical	9235954
ATF2_HUMAN	ATF2	physical	12761180
NOXA1_HUMAN	NOXA1	physical	20110267
TAU_HUMAN	MAPT	physical	9199504
MAPK3_HUMAN	MAPKAPK3	physical	21988832
MK14_HUMAN	MAPK14	physical	23602568
MAPK2_HUMAN	MAPKAPK2	physical	23602568
MAPK3_HUMAN	MAPKAPK3	physical	23602568
OBSL1_HUMAN	OBSL1	physical	23602568
MKNK1_HUMAN	MKNK1	physical	23602568
DUS9_HUMAN	DUSP9	physical	23602568
SYVC_HUMAN	VARS	physical	23602568
CUL7_HUMAN	CUL7	physical	23602568
CCDC8_HUMAN	CCDC8	physical	23602568
RHG12_HUMAN	ARHGAP12	physical	23602568
MAPK2_HUMAN	MAPKAPK2	physical	11551945
HDAC1_HUMAN	HDAC1	physical	26344197
PPM1G_HUMAN	PPM1G	physical	26344197
TAB1_HUMAN	TAB1	physical	25241761

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
• DB08896: Regorafenib

Related Literatures of Post-Translational Modification

Phosphorylation

"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 TYR-182, AND MASSSPECTROMETRY.
PubMed: 19369195

"Global survey of phosphotyrosine signaling identifies oncogenickinases in lung cancer.";
Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J.,Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L.,Mitchell J., Wetzel R., Macneill J., Ren J.M., Yuan J.,Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X.,Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J.;
Cell 131:1190-1203(2007).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-182, AND MASSSPECTROMETRY.
PubMed: 18083107