dbPTM

RIPK2_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	RIPK2_HUMAN
UniProt AC	O43353
Protein Name	Receptor-interacting serine/threonine-protein kinase 2
Gene Name	RIPK2
Organism	Homo sapiens (Human).
Sequence Length	540
Subcellular Localization	Cytoplasm .
Protein Description	Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation..
Protein Sequence	MNGEAICSALPTIPYHKLADLRYLSRGASGTVSSARHADWRVQVAVKHLHIHTPLLDSERKDVLREAEILHKARFSYILPILGICNEPEFLGIVTEYMPNGSLNELLHRKTEYPDVAWPLRFRILHEIALGVNYLHNMTPPLLHHDLKTQNILLDNEFHVKIADFGLSKWRMMSLSQSRSSKSAPEGGTIIYMPPENYEPGQKSRASIKHDIYSYAVITWEVLSRKQPFEDVTNPLQIMYSVSQGHRPVINEESLPYDIPHRARMISLIESGWAQNPDERPSFLKCLIELEPVLRTFEEITFLEAVIQLKKTKLQSVSSAIHLCDKKKMELSLNIPVNHGPQEESCGSSQLHENSGSPETSRSLPAPQDNDFLSRKAQDCYFMKLHHCPGNHSWDSTISGSQRAAFCDHKTTPCSSAIINPLSTAGNSERLQPGIAQQWIQSKREDIVNQMTEACLNQSLDALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKDNKQMGLQPYPEILVVSRSPSLNLLQNKSM

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
17	Ubiquitination	LPTIPYHKLADLRYL CCCCCHHHHHCHHHH	39.26	-
23	Phosphorylation	HKLADLRYLSRGASG HHHHCHHHHHCCCCC	19.14	-
26	Methylation	ADLRYLSRGASGTVS HCHHHHHCCCCCCCC	41.94	115491285
29	Phosphorylation	RYLSRGASGTVSSAR HHHHCCCCCCCCCCH	37.51	28857561
45 (in isoform 2)	Ubiquitination	-	6.37	21906983
66 (in isoform 2)	Ubiquitination	-	46.63	21906983
149	Acetylation	LLHHDLKTQNILLDN CCCCCCCCCCEEECC	33.86	22520462
168	Phosphorylation	KIADFGLSKWRMMSL EEHHHCCCHHHHHHH	30.47	21082442
174	Acetylation	LSKWRMMSLSQSRSS CCHHHHHHHHHCCCC	18.61	22520462
174	Phosphorylation	LSKWRMMSLSQSRSS CCHHHHHHHHHCCCC	18.61	21082442
176	Phosphorylation	KWRMMSLSQSRSSKS HHHHHHHHHCCCCCC	20.85	17525332
176	Acetylation	KWRMMSLSQSRSSKS HHHHHHHHHCCCCCC	20.85	22520462
178	Acetylation	RMMSLSQSRSSKSAP HHHHHHHCCCCCCCC	30.65	22520462
178	Phosphorylation	RMMSLSQSRSSKSAP HHHHHHHCCCCCCCC	30.65	22617229
180	Phosphorylation	MSLSQSRSSKSAPEG HHHHHCCCCCCCCCC	47.57	29514088
181	Phosphorylation	SLSQSRSSKSAPEGG HHHHCCCCCCCCCCC	29.53	22322096
181	Acetylation	SLSQSRSSKSAPEGG HHHHCCCCCCCCCCC	29.53	22520462
182	Ubiquitination	LSQSRSSKSAPEGGT HHHCCCCCCCCCCCE	52.46	21906983
182 (in isoform 1)	Ubiquitination	-	52.46	21906983
183	Acetylation	SQSRSSKSAPEGGTI HHCCCCCCCCCCCEE	51.51	22520462
183	Phosphorylation	SQSRSSKSAPEGGTI HHCCCCCCCCCCCEE	51.51	28348404
189	Acetylation	KSAPEGGTIIYMPPE CCCCCCCEEEECCCC	18.30	22520462
189	Phosphorylation	KSAPEGGTIIYMPPE CCCCCCCEEEECCCC	18.30	28348404
203 (in isoform 1)	Ubiquitination	-	48.07	21906983
203	Ubiquitination	ENYEPGQKSRASIKH CCCCCCCCCCHHHCC	48.07	21906983
209	Ubiquitination	QKSRASIKHDIYSYA CCCCHHHCCHHHHHH	32.50	PubMed
282	Phosphorylation	QNPDERPSFLKCLIE CCCCCCCCHHHHHHH	49.81	24719451
318	Phosphorylation	KTKLQSVSSAIHLCD HHCHHHHHHHHHHCC	21.21	28857561
319	Phosphorylation	TKLQSVSSAIHLCDK HCHHHHHHHHHHCCC	29.14	28857561
332	Phosphorylation	DKKKMELSLNIPVNH CCCCCEEEEECCCCC	13.18	28270605
345	Phosphorylation	NHGPQEESCGSSQLH CCCCCCCCCCCCCCC	24.03	23401153
348	Phosphorylation	PQEESCGSSQLHENS CCCCCCCCCCCCCCC	21.16	18691976
349	Phosphorylation	QEESCGSSQLHENSG CCCCCCCCCCCCCCC	23.26	25159151
355	Phosphorylation	SSQLHENSGSPETSR CCCCCCCCCCCCHHC	37.35	29978859
357	Phosphorylation	QLHENSGSPETSRSL CCCCCCCCCCHHCCC	21.27	25159151
360	Phosphorylation	ENSGSPETSRSLPAP CCCCCCCHHCCCCCC	32.59	29978859
361	Phosphorylation	NSGSPETSRSLPAPQ CCCCCCHHCCCCCCC	20.43	29978859
363	Phosphorylation	GSPETSRSLPAPQDN CCCCHHCCCCCCCCC	38.17	29255136
363	Acetylation	GSPETSRSLPAPQDN CCCCHHCCCCCCCCC	38.17	22520462
374	Phosphorylation	PQDNDFLSRKAQDCY CCCCCHHHHHHHHEE	31.56	28857561
381	Phosphorylation	SRKAQDCYFMKLHHC HHHHHHEEEEECCCC	18.26	27273156
384	Methylation	AQDCYFMKLHHCPGN HHHEEEEECCCCCCC	34.47	115976745
393	Phosphorylation	HHCPGNHSWDSTISG CCCCCCCCCCCCCCH	36.26	23927012
396	Phosphorylation	PGNHSWDSTISGSQR CCCCCCCCCCCHHHC	22.76	23927012
397	Acetylation	GNHSWDSTISGSQRA CCCCCCCCCCHHHCC	19.38	22520462
397	Phosphorylation	GNHSWDSTISGSQRA CCCCCCCCCCHHHCC	19.38	23927012
399	Phosphorylation	HSWDSTISGSQRAAF CCCCCCCCHHHCCCC	32.26	23927012
401	Phosphorylation	WDSTISGSQRAAFCD CCCCCCHHHCCCCCC	15.09	23927012
410	Ubiquitination	RAAFCDHKTTPCSSA CCCCCCCCCCCCCHH	40.62	-
411	Phosphorylation	AAFCDHKTTPCSSAI CCCCCCCCCCCCHHC	32.33	25159151
412	Phosphorylation	AFCDHKTTPCSSAII CCCCCCCCCCCHHCC	27.40	25159151
415	Phosphorylation	DHKTTPCSSAIINPL CCCCCCCCHHCCCCC	24.81	28348404
416	Phosphorylation	HKTTPCSSAIINPLS CCCCCCCHHCCCCCC	30.15	28348404
423	Acetylation	SAIINPLSTAGNSER HHCCCCCCCCCCCHH	19.91	22520462
428	Phosphorylation	PLSTAGNSERLQPGI CCCCCCCCHHCCCCH	24.15	28348404
459	Phosphorylation	TEACLNQSLDALLSR HHHHHHHHHHHHHCC	27.43	22210691
474	Phosphorylation	DLIMKEDYELVSTKP CHHHHCCCEEECCCC	16.56	21123652
478	Phosphorylation	KEDYELVSTKPTRTS HCCCEEECCCCCCHH	43.25	27251275
479	Phosphorylation	EDYELVSTKPTRTSK CCCEEECCCCCCHHH	33.30	27251275
480	Ubiquitination	DYELVSTKPTRTSKV CCEEECCCCCCHHHH	36.56	-
482	Phosphorylation	ELVSTKPTRTSKVRQ EEECCCCCCHHHHHH	48.40	30576142
484	Phosphorylation	VSTKPTRTSKVRQLL ECCCCCCHHHHHHHH	35.06	27251275
485	Phosphorylation	STKPTRTSKVRQLLD CCCCCCHHHHHHHHH	26.34	28348404
508	Ubiquitination	FAKVIVQKLKDNKQM HHHHHHHHHHHCCCC	46.76	-
520	Phosphorylation	KQMGLQPYPEILVVS CCCCCCCCCEEEEEE	10.67	18691976
527	Phosphorylation	YPEILVVSRSPSLNL CCEEEEEECCCCHHH	21.40	25159151
529	Phosphorylation	EILVVSRSPSLNLLQ EEEEEECCCCHHHHH	16.01	30266825
531	Phosphorylation	LVVSRSPSLNLLQNK EEEECCCCHHHHHCC	31.01	25159151
538	Ubiquitination	SLNLLQNKSM----- CHHHHHCCCC-----	34.63	-
539	Phosphorylation	LNLLQNKSM------ HHHHHCCCC------	36.96	17054981

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
174	S	Phosphorylation	Kinase	RIPK2	O43353	PSP
176	S	Phosphorylation	Kinase	RIPK2	O43353	PSP
178	S	Phosphorylation	Kinase	RIPK2	O43353	PSP
180	S	Phosphorylation	Kinase	RIPK2	O43353	PSP
181	S	Phosphorylation	Kinase	RIPK2	O43353	PSP
381	Y	Phosphorylation	Kinase	CSK	P41240	Uniprot
474	Y	Phosphorylation	Kinase	RIPK2	O43353	PSP
-	K	Ubiquitination	E3 ubiquitin ligase	BIRC2	Q13490	PMID:21931591
-	K	Ubiquitination	E3 ubiquitin ligase	BIRC3	Q13489	PMID:21931591
-	K	Ubiquitination	E3 ubiquitin ligase	XIAP	P98170	PMID:23818254
-	K	Ubiquitination	E3 ubiquitin ligase	PELI3	Q8N2H9	PMID:23892723
-	K	Ubiquitination	E3 ubiquitin ligase	TRAF6	Q9Y4K3	PMID:17947236
-	K	Ubiquitination	E3 ubiquitin ligase	ITCH	Q96J02	PMID:19592251

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
48	K	ubiquitylation	21931591
Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B.
174	S	Acetylation	22520462
(Microbial infection) Acetylation of Ser-174, Ser-176 and Ser-178 by Yersinia YopJ prevents phosphorylation and activation, thereby promoting cell death.
174	S	Phosphorylation	22520462
(Microbial infection) Acetylation of Ser-174, Ser-176 and Ser-178 by Yersinia YopJ prevents phosphorylation and activation, thereby promoting cell death.
176	S	Acetylation	16824733
(Microbial infection) Acetylation of Ser-174, Ser-176 and Ser-178 by Yersinia YopJ prevents phosphorylation and activation, thereby promoting cell death.
176	S	Phosphorylation	16824733
(Microbial infection) Acetylation of Ser-174, Ser-176 and Ser-178 by Yersinia YopJ prevents phosphorylation and activation, thereby promoting cell death.
178	S	Acetylation	22520462
(Microbial infection) Acetylation of Ser-174, Ser-176 and Ser-178 by Yersinia YopJ prevents phosphorylation and activation, thereby promoting cell death.
178	S	Phosphorylation	22520462
(Microbial infection) Acetylation of Ser-174, Ser-176 and Ser-178 by Yersinia YopJ prevents phosphorylation and activation, thereby promoting cell death.
209	K	ubiquitylation	18079694
Ubiquitinated on Lys-209; undergoes 'Lys-63'-linked polyubiquitination catalyzed by ITCH.

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 RIPK2_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
KCD12_HUMAN	KCTD12	physical	17353931
PHB2_HUMAN	PHB2	physical	17353931
RS14_HUMAN	RPS14	physical	17353931
RL38_HUMAN	RPL38	physical	17353931
CFLAR_HUMAN	CFLAR	physical	9575181
TRAF5_HUMAN	TRAF5	physical	9642260
TRAF6_HUMAN	TRAF6	physical	9642260
BIRC2_HUMAN	BIRC2	physical	9642260
TNR1A_HUMAN	TNFRSF1A	physical	9642260
TRAF2_HUMAN	TRAF2	physical	9705938
NEMO_HUMAN	IKBKG	physical	10880512
BIRC3_HUMAN	BIRC3	physical	19464198
BIRC2_HUMAN	BIRC2	physical	19464198
NEMO_HUMAN	IKBKG	physical	18079694
M3K7_HUMAN	MAP3K7	physical	18079694
TAB1_HUMAN	TAB1	physical	18079694
TAB2_HUMAN	TAB2	physical	18079694
TRAF2_HUMAN	TRAF2	physical	21903422
NOD2_HUMAN	NOD2	physical	15620648
NOD2_HUMAN	NOD2	physical	21123652
RIPK2_HUMAN	RIPK2	physical	21123652
NAT16_HUMAN	NAT16	physical	22607974
XIAP_HUMAN	XIAP	physical	22607974
RIPK1_HUMAN	RIPK1	physical	22607974
RNF31_HUMAN	RNF31	physical	22607974
CASPC_HUMAN	CASP12	physical	18329614
TRAF6_HUMAN	TRAF6	physical	18329614
XIAP_HUMAN	XIAP	physical	19667203
LRRK2_HUMAN	LRRK2	physical	20949042
M3K7_HUMAN	MAP3K7	physical	17947236
UBC_HUMAN	UBC	physical	23437331
XIAP_HUMAN	XIAP	physical	22815893
NOD1_HUMAN	NOD1	physical	16517750
PELI3_HUMAN	PELI3	physical	23892723
KDM3A_HUMAN	KDM3A	physical	23455924
ANM2_HUMAN	PRMT2	physical	23455924
TRAF3_HUMAN	TRAF3	physical	23333941
RIPK2_HUMAN	RIPK2	physical	25416956
IRF4_HUMAN	IRF4	physical	24670424
RIPK2_HUMAN	RIPK2	physical	27045108

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 RIPK2_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-168; SER-174; SER-176;SER-178; SER-332; SER-345; SER-349; SER-355; THR-360; SER-363;TYR-381; SER-393; SER-527; SER-529; SER-531 AND SER-539, AND MASSSPECTROMETRY.	19369195 [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-531, AND MASSSPECTROMETRY.	18669648 [Abstract]
"Kinase-selective enrichment enables quantitative phosphoproteomics ofthe kinome across the cell cycle."; Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,Greff Z., Keri G., Stemmann O., Mann M.; Mol. Cell 31:438-448(2008). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-168; SER-176; SER-178;SER-363; SER-527; SER-529; SER-531 AND SER-539, AND MASS SPECTROMETRY.	18691976 [Abstract]
"ATM and ATR substrate analysis reveals extensive protein networksresponsive to DNA damage."; Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.; Science 316:1160-1166(2007). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-176, AND MASSSPECTROMETRY.	17525332 [Abstract]
"Proteomics analysis of protein kinases by target class-selectiveprefractionation and tandem mass spectrometry."; Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R.,Keri G., Wehland J., Daub H.; Mol. Cell. Proteomics 6:537-547(2007). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-531, AND MASSSPECTROMETRY.	17192257 [Abstract]
"Identification of a regulatory autophosphorylation site in theserine-threonine kinase RIP2."; Dorsch M., Wang A., Cheng H., Lu C., Bielecki A., Charron K.,Clauser K., Ren H., Polakiewicz R.D., Parsons T., Li P., Ocain T.,Xu Y.; Cell. Signal. 18:2223-2229(2006). Cited for: AUTOPHOSPHORYLATION AT SER-176.	16824733 [Abstract]

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