dbPTM

IKKE_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	IKKE_HUMAN
UniProt AC	Q14164
Protein Name	Inhibitor of nuclear factor kappa-B kinase subunit epsilon
Gene Name	IKBKE
Organism	Homo sapiens (Human).
Sequence Length	716
Subcellular Localization	Cytoplasm . Nucleus. Nucleus, PML body . Targeting to PML nuclear bodies upon DNA damage is TOPORS-dependent (PubMed:20188669). Located diffusely throughout the cytoplasm but locates to punctate cytoplasmic bodies when coexpressed with TRIM6 (PubMed:
Protein Description	Serine/threonine kinase that plays an essential role in regulating inflammatory responses to viral infection, through the activation of the type I IFN, NF-kappa-B and STAT signaling. Also involved in TNFA and inflammatory cytokines, like Interleukin-1, signaling. Following activation of viral RNA sensors, such as RIG-I-like receptors, associates with DDX3X and phosphorylates interferon regulatory factors (IRFs), IRF3 and IRF7, as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRF3 leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNB. In order to establish such an antiviral state, IKBKE forms several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including IPS1/MAVS, TANK, AZI2/NAP1 or TBKBP1/SINTBAD can be recruited to the IKBKE-containing-complexes. Activated by polyubiquitination in response to TNFA and interleukin-1, regulates the NF-kappa-B signaling pathway through, at least, the phosphorylation of CYLD. Phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. In addition, is also required for the induction of a subset of ISGs which displays antiviral activity, may be through the phosphorylation of STAT1 at 'Ser-708'. Phosphorylation of STAT1 at 'Ser-708' seems also to promote the assembly and DNA binding of ISGF3 (STAT1:STAT2:IRF9) complexes compared to GAF (STAT1:STAT1) complexes, in this way regulating the balance between type I and type II IFN responses. Protects cells against DNA damage-induced cell death. Also plays an important role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Phosphorylates AKT1..
Protein Sequence	MQSTANYLWHTDDLLGQGATASVYKARNKKSGELVAVKVFNTTSYLRPREVQVREFEVLRKLNHQNIVKLFAVEETGGSRQKVLVMEYCSSGSLLSVLESPENAFGLPEDEFLVVLRCVVAGMNHLRENGIVHRDIKPGNIMRLVGEEGQSIYKLTDFGAARELDDDEKFVSVYGTEEYLHPDMYERAVLRKPQQKAFGVTVDLWSIGVTLYHAATGSLPFIPFGGPRRNKEIMYRITTEKPAGAIAGAQRRENGPLEWSYTLPITCQLSLGLQSQLVPILANILEVEQAKCWGFDQFFAETSDILQRVVVHVFSLSQAVLHHIYIHAHNTIAIFQEAVHKQTSVAPRHQEYLFEGHLCVLEPSVSAQHIAHTTASSPLTLFSTAIPKGLAFRDPALDVPKFVPKVDLQADYNTAKGVLGAGYQALRLARALLDGQELMFRGLHWVMEVLQATCRRTLEVARTSLLYLSSSLGTERFSSVAGTPEIQELKAAAELRSRLRTLAEVLSRCSQNITETQESLSSLNRELVKSRDQVHEDRSIQQIQCCLDKMNFIYKQFKKSRMRPGLGYNEEQIHKLDKVNFSHLAKRLLQVFQEECVQKYQASLVTHGKRMRVVHETRNHLRLVGCSVAACNTEAQGVQESLSKLLEELSHQLLQDRAKGAQASPPPIAPYPSPTRKDLLLHMQELCEGMKLLASDLLDNNRIIERLNRVPAPPDV

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
25	Ubiquitination	GATASVYKARNKKSG CCCEEHEHHCCCCCC	38.42	-
30	Ubiquitination	VYKARNKKSGELVAV HEHHCCCCCCCEEEE	68.21	PubMed
61	Ubiquitination	REFEVLRKLNHQNIV CHHHHHHHCCCCCCE	49.86	-
137	Ubiquitination	GIVHRDIKPGNIMRL CCCCCCCCCCCCEEE	51.68	2190698
153	Phosphorylation	GEEGQSIYKLTDFGA CCCCCCEEEECCCCC	12.75	-
154	Ubiquitination	EEGQSIYKLTDFGAA CCCCCEEEECCCCCC	43.15	-
172	Phosphorylation	DDDEKFVSVYGTEEY CCCCCEEEECCCCCC	16.86	22322096
174	Phosphorylation	DEKFVSVYGTEEYLH CCCEEEECCCCCCCC	15.72	29978859
176	Phosphorylation	KFVSVYGTEEYLHPD CEEEECCCCCCCCCH	14.14	28348404
179	Phosphorylation	SVYGTEEYLHPDMYE EECCCCCCCCCHHHH	12.22	29978859
231	Ubiquitination	FGGPRRNKEIMYRIT CCCCCCCCEEEEEEE	46.97	-
231	Sumoylation	FGGPRRNKEIMYRIT CCCCCCCCEEEEEEE	46.97	20188669
231	Sumoylation	FGGPRRNKEIMYRIT CCCCCCCCEEEEEEE	46.97	-
241	Ubiquitination	MYRITTEKPAGAIAG EEEEECCCCCCCCCC	37.77	-
401	Ubiquitination	DPALDVPKFVPKVDL CCCCCCCCCCCCCEE	59.86	PubMed
416	Ubiquitination	QADYNTAKGVLGAGY CCCCHHHHHHHHHHH	47.73	PubMed
463	Phosphorylation	RTLEVARTSLLYLSS HHHHHHHHHHHHHHC	17.62	-
464	Phosphorylation	TLEVARTSLLYLSSS HHHHHHHHHHHHHCC	15.72	-
474	Phosphorylation	YLSSSLGTERFSSVA HHHCCCCCCCHHHCC	29.31	24719451
478	Phosphorylation	SLGTERFSSVAGTPE CCCCCCHHHCCCCHH	30.08	28857561
479	Phosphorylation	LGTERFSSVAGTPEI CCCCCHHHCCCCHHH	17.18	28857561
490	Ubiquitination	TPEIQELKAAAELRS CHHHHHHHHHHHHHH	34.92	-
501	Phosphorylation	ELRSRLRTLAEVLSR HHHHHHHHHHHHHHH	34.61	24882218
519	Phosphorylation	NITETQESLSSLNRE CHHHHHHHHHHHHHH	24.59	30266825
521	Phosphorylation	TETQESLSSLNRELV HHHHHHHHHHHHHHH	41.90	30266825
522	Phosphorylation	ETQESLSSLNRELVK HHHHHHHHHHHHHHH	34.65	30266825
549	Ubiquitination	QIQCCLDKMNFIYKQ HHHHHHHHHHHHHHH	23.85	-
554	Phosphorylation	LDKMNFIYKQFKKSR HHHHHHHHHHHHHHC	8.46	29083192
578	Ubiquitination	EQIHKLDKVNFSHLA HHHHHHHHCCHHHHH	49.90	-
603	Phosphorylation	CVQKYQASLVTHGKR HHHHHHHHHHHCCCC	14.09	25690035
606	Phosphorylation	KYQASLVTHGKRMRV HHHHHHHHCCCCCEE	30.15	25690035
609	Ubiquitination	ASLVTHGKRMRVVHE HHHHHCCCCCEEEEC	35.10	-
664	Phosphorylation	RAKGAQASPPPIAPY HHCCCCCCCCCCCCC	26.34	25159151
671	Phosphorylation	SPPPIAPYPSPTRKD CCCCCCCCCCCCHHH	13.81	24732914
673	Phosphorylation	PPIAPYPSPTRKDLL CCCCCCCCCCHHHHH	32.81	25159151
675	Phosphorylation	IAPYPSPTRKDLLLH CCCCCCCCHHHHHHH	55.47	24732914
677	Ubiquitination	PYPSPTRKDLLLHMQ CCCCCCHHHHHHHHH	56.03	-

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
153	Y	Phosphorylation	Kinase	EGFR	P00533	PSP
172	S	Phosphorylation	Kinase	IKBKB	O14920	GPS
172	S	Phosphorylation	Kinase	MAP2K-FAMILY	-	GPS
179	Y	Phosphorylation	Kinase	EGFR	P00533	PSP
501	T	Phosphorylation	Kinase	IKKE	Q14164	PSP
-	K	Ubiquitination	E3 ubiquitin ligase	BIRC2	Q13490	PMID:23453969
-	K	Ubiquitination	E3 ubiquitin ligase	TANK	Q92844	PMID:23453969
-	K	Ubiquitination	E3 ubiquitin ligase	BIRC3	Q13489	PMID:22199232
-	K	Ubiquitination	E3 ubiquitin ligase	TRAF3	Q13114	PMID:23308279

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
30	K	ubiquitylation	23453969
'Lys-63'-linked polyubiquitinated at Lys-30 and Lys-401 by TRAF2:BIRC2 and TRAF2:BIRC3 complexes.
172	S	Phosphorylation	10421793
Phosphorylation at Ser-172 is enhanced by the interaction with DDX3X.
401	K	ubiquitylation	23453969
'Lys-63'-linked polyubiquitinated at Lys-30 and Lys-401 by TRAF2:BIRC2 and TRAF2:BIRC3 complexes.
501	T	Phosphorylation	24882218
Phosphorylated at Thr-501 upon IFN activation.

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 IKKE_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
ROCK2_HUMAN	ROCK2	physical	17353931
CLH1_HUMAN	CLTC	physical	17353931
LPPRC_HUMAN	LRPPRC	physical	17353931
DUSTY_HUMAN	DSTYK	physical	17353931
SYEP_HUMAN	EPRS	physical	17353931
IMDH2_HUMAN	IMPDH2	physical	17353931
MYH10_HUMAN	MYH10	physical	17353931
PABP1_HUMAN	PABPC1	physical	17353931
ACLY_HUMAN	ACLY	physical	17353931
PUR9_HUMAN	ATIC	physical	17353931
TERA_HUMAN	VCP	physical	17353931
PLST_HUMAN	PLS3	physical	17353931
2AAA_HUMAN	PPP2R1A	physical	17353931
RUVB2_HUMAN	RUVBL2	physical	17353931
SYLC_HUMAN	LARS	physical	17353931
PSA7_HUMAN	PSMA7	physical	17353931
PDIA6_HUMAN	PDIA6	physical	17353931
SND1_HUMAN	SND1	physical	17353931
HYOU1_HUMAN	HYOU1	physical	17353931
CDC37_HUMAN	CDC37	physical	14743216
FKBP5_HUMAN	FKBP5	physical	14743216
KTN1_HUMAN	KTN1	physical	14743216
TANK_HUMAN	TANK	physical	10759890
CYLD_HUMAN	CYLD	physical	18636086
IRF3_HUMAN	IRF3	physical	18636086
TF65_HUMAN	RELA	physical	15489227
CACO2_HUMAN	CALCOCO2	physical	19820708
CDC37_HUMAN	CDC37	physical	21903422
MAVS_HUMAN	MAVS	physical	21903422
TNIP1_HUMAN	TNIP1	physical	21885437
TNAP3_HUMAN	TNFAIP3	physical	21885437
TNAP3_HUMAN	TNFAIP3	physical	15661910
MBP_HUMAN	MBP	physical	17599067
XIAP_HUMAN	XIAP	physical	22072751
IRF3_HUMAN	IRF3	physical	22072751
MAVS_HUMAN	MAVS	physical	21200404
TOPRS_HUMAN	TOPORS	physical	20188669
TRI27_HUMAN	TRIM27	physical	16393995
TRAF3_HUMAN	TRAF3	physical	22079989
TRAF2_HUMAN	TRAF2	physical	23007157
IKBA_HUMAN	NFKBIA	physical	20449947
RNF11_HUMAN	RNF11	physical	23308279
TRAF3_HUMAN	TRAF3	physical	23308279
DDX3X_HUMAN	DDX3X	physical	18636090
IKKB_HUMAN	IKBKB	physical	23453969
NEMO_HUMAN	IKBKG	physical	23453969
MYD88_HUMAN	MYD88	physical	23453969
IKKE_HUMAN	IKBKE	physical	23453969
BIRC2_HUMAN	BIRC2	physical	23453969
TRAF2_HUMAN	TRAF2	physical	23453969
CIKS_HUMAN	TRAF3IP2	physical	22851696
TRAF3_HUMAN	TRAF3	physical	24763515
NMRL1_HUMAN	NMRAL1	physical	24763515
TRIM6_HUMAN	TRIM6	physical	24882218
UBC_HUMAN	UBC	physical	24882218
UBC_HUMAN	UBC	physical	19380491
APBP2_HUMAN	APPBP2	physical	25852190
TCPB_HUMAN	CCT2	physical	25852190
TCPG_HUMAN	CCT3	physical	25852190
TCPD_HUMAN	CCT4	physical	25852190
TCPE_HUMAN	CCT5	physical	25852190
TCPZ_HUMAN	CCT6A	physical	25852190
TCPQ_HUMAN	CCT8	physical	25852190
TANK_HUMAN	TANK	physical	25852190
TCPA_HUMAN	TCP1	physical	25852190
TRAF2_HUMAN	TRAF2	physical	25852190
IFIT3_HUMAN	IFIT3	physical	21813773
IRF3_HUMAN	IRF3	physical	27622505
UBC_HUMAN	UBC	physical	27622505
YAP1_HUMAN	YAP1	physical	28346439
IRF3_HUMAN	IRF3	physical	28346439

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 IKKE_HUMAN

Related Literatures of Post-Translational Modification

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-664 AND SER-673, ANDMASS SPECTROMETRY.	19369195 [Abstract]

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