MK14_MOUSE - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: MK14_MOUSE
• UniProt AC: P47811
• Protein Name: Mitogen-activated protein kinase 14
• Gene Name: Mapk14
• Organism: Mus musculus (Mouse).
• Sequence Length: 360
• Subcellular Localization: Cytoplasm . Nucleus .
• Protein Description: Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 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. 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. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. 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. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. 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. Another p38 MAPK substrate is 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. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Phosphorylates S100A9 at 'Thr-113' (By similarity)..
• Protein Sequence: MSQERPTFYRQELNKTIWEVPERYQNLSPVGSGAYGSVCAAFDTKTGHRVAVKKLSRPFQSIIHAKRTYRELRLLKHMKHENVIGLLDVFTPARSLEEFNDVYLVTHLMGADLNNIVKCQKLTDDHVQFLIYQILRGLKYIHSADIIHRDLKPSNLAVNEDCELKILDFGLARHTDDEMTGYVATRWYRAPEIMLNWMHYNQTVDIWSVGCIMAELLTGRTLFPGTDHIDQLKLILRLVGTPGAELLKKISSESARNYIQSLAQMPKMNFANVFIGANPLAVDLLEKMLVLDSDKRITAAQALAHAYFAQYHDPDDEPVADPYDQSFESRDLLIDEWKSLTYDEVISFVPPPLDQEEMES

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
2	Phosphorylation	------MSQERPTFY ------CCCCCCCCC	40.52	26824392
2	Acetylation	------MSQERPTFY ------CCCCCCCCC	40.52	-
7	Phosphorylation	-MSQERPTFYRQELN -CCCCCCCCCHHHHH	39.25	26160508
9	Phosphorylation	SQERPTFYRQELNKT CCCCCCCCHHHHHHH	17.54	26160508
15	Ubiquitination	FYRQELNKTIWEVPE CCHHHHHHHHHHCHH	54.75	22790023
16	Phosphorylation	YRQELNKTIWEVPER CHHHHHHHHHHCHHH	30.19	26745281
24	Phosphorylation	IWEVPERYQNLSPVG HHHCHHHHCCCCCCC	10.49	26745281
28	Phosphorylation	PERYQNLSPVGSGAY HHHHCCCCCCCCCCC	25.70	26643407
32	Phosphorylation	QNLSPVGSGAYGSVC CCCCCCCCCCCCCCE	22.08	26745281
35	Phosphorylation	SPVGSGAYGSVCAAF CCCCCCCCCCCEEEE	17.29	26745281
37	Phosphorylation	VGSGAYGSVCAAFDT CCCCCCCCCEEEEEC	11.01	26745281
53	Acetylation	TGHRVAVKKLSRPFQ CCCEEEEECCCCCHH	37.95	-
139	Ubiquitination	YQILRGLKYIHSADI HHHHHHCCHHHHHCE	45.01	22790023
143	Phosphorylation	RGLKYIHSADIIHRD HHCCHHHHHCEECCC	20.34	-
152	Acetylation	DIIHRDLKPSNLAVN CEECCCCCHHHCCCC	51.17	-
162	Glutathionylation	NLAVNEDCELKILDF HCCCCCCCEEEEEEE	5.56	24333276
165	Ubiquitination	VNEDCELKILDFGLA CCCCCEEEEEEEEEC	20.94	22790023
175	Phosphorylation	DFGLARHTDDEMTGY EEEECCCCCCCHHHH	39.32	22322096
179	Oxidation	ARHTDDEMTGYVATR CCCCCCCHHHHHHCC	4.54	17242355
180	Phosphorylation	RHTDDEMTGYVATRW CCCCCCHHHHHHCCC	24.26	16563375
182	Phosphorylation	TDDEMTGYVATRWYR CCCCHHHHHHCCCEE	4.26	16563375
185	Phosphorylation	EMTGYVATRWYRAPE CHHHHHHCCCEECCH	16.22	27087446
241 (in isoform 3)	Phosphorylation	-	15.86	22942356
248	Ubiquitination	TPGAELLKKISSESA CCHHHHHHHHCCHHH	61.76	22790023
323	Phosphorylation	DEPVADPYDQSFESR CCCCCCCCCCCHHHH	27.45	19011223

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	P38A	Q16539	PSP
180	T	Phosphorylation	Kinase	MAPK14	P47811	GPS
180	T	Phosphorylation	Kinase	MAP2K3	O09110	Uniprot
180	T	Phosphorylation	Kinase	MAP2K4	P47809	Uniprot
180	T	Phosphorylation	Kinase	MAP2K6	P52564	GPS
180	T	Phosphorylation	Kinase	MAP2K6	P70236	Uniprot
182	Y	Phosphorylation	Kinase	ABL1	P00519	GPS
182	Y	Phosphorylation	Kinase	P38A	Q16539	PSP
182	Y	Phosphorylation	Kinase	MAPK14	P47811	GPS
182	Y	Phosphorylation	Kinase	MAP2K3	O09110	Uniprot
182	Y	Phosphorylation	Kinase	MAP2K4	P47809	Uniprot
182	Y	Phosphorylation	Kinase	MAP2K6	P52564	GPS
182	Y	Phosphorylation	Kinase	MAP2K6	P70236	Uniprot
323	Y	Phosphorylation	Kinase	ABL1	P00519	GPS
323	Y	Phosphorylation	Kinase	ZAP70	P43403	PSP
323	Y	Phosphorylation	Kinase	ZAP70	P43404	Uniprot

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
53	K	Acetylation	Acetylated at Lys-53 and Lys-152 by KAT2B and EP300.	-
53	K	Acetylation	Acetylation at Lys-53 increases the affinity for ATP and enhances kinase activity.	-
53	K	Acetylation	Lys-53 and Lys-152 are deacetylated by HDAC3 (By similarity).	-
152	K	Acetylation	Acetylated at Lys-53 and Lys-152 by KAT2B and EP300.	-
152	K	Acetylation	Lys-53 and Lys-152 are deacetylated by HDAC3 (By similarity).	-
180	T	Phosphorylation	Dually phosphorylated on Thr-180 and Tyr-182 by the MAP2Ks MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6 in response to inflammatory cytokines, environmental stress or growth factors, which activates the enzyme.	17947660

Disease-associated PTM Sites based on SAP

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

Oops, there are no SNP-PTM records of MK14_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
DUS4_HUMAN	DUSP4	physical	11062068
MP2K6_HUMAN	MAP2K6	physical	11062068
MP2K3_HUMAN	MAP2K3	physical	11062068
STK39_MOUSE	Stk39	physical	12386165
CEBPB_MOUSE	Cebpb	physical	21847090
SP20H_MOUSE	Supt20	physical	16751104
SP20H_HUMAN	SUPT20H	physical	16751104
MAPK2_MOUSE	Mapkapk2	physical	15538386
JIP4_MOUSE	Spag9	physical	15767678
ATF2_MOUSE	Atf2	physical	15767678
SHC1_MOUSE	Shc1	physical	16251354
ATF2_MOUSE	Atf2	physical	15192015
HSPB2_MOUSE	Hspb2	physical	17015449
MAPK2_HUMAN	MAPKAPK2	physical	15287722

Drug and Disease Associations

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