dbPTM

RET_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	RET_HUMAN
UniProt AC	P07949
Protein Name	Proto-oncogene tyrosine-protein kinase receptor Ret {ECO:0000305}
Gene Name	RET {ECO:0000312\|HGNC:HGNC:9967}
Organism	Homo sapiens (Human).
Sequence Length	1114
Subcellular Localization	Cell membrane Single-pass type I membrane protein . Endosome membrane Single-pass type I membrane protein .
Protein Description	Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration. Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which induces inhibition of food-intake. Activates MAPK- and AKT-signaling pathways. [PubMed: 28846097]
Protein Sequence	MAKATSGAAGLRLLLLLLLPLLGKVALGLYFSRDAYWEKLYVDQAAGTPLLYVHALRDAPEEVPSFRLGQHLYGTYRTRLHENNWICIQEDTGLLYLNRSLDHSSWEKLSVRNRGFPLLTVYLKVFLSPTSLREGECQWPGCARVYFSFFNTSFPACSSLKPRELCFPETRPSFRIRENRPPGTFHQFRLLPVQFLCPNISVAYRLLEGEGLPFRCAPDSLEVSTRWALDREQREKYELVAVCTVHAGAREEVVMVPFPVTVYDEDDSAPTFPAGVDTASAVVEFKRKEDTVVATLRVFDADVVPASGELVRRYTSTLLPGDTWAQQTFRVEHWPNETSVQANGSFVRATVHDYRLVLNRNLSISENRTMQLAVLVNDSDFQGPGAGVLLLHFNVSVLPVSLHLPSTYSLSVSRRARRFAQIGKVCVENCQAFSGINVQYKLHSSGANCSTLGVVTSAEDTSGILFVNDTKALRRPKCAELHYMVVATDQQTSRQAQAQLLVTVEGSYVAEEAGCPLSCAVSKRRLECEECGGLGSPTGRCEWRQGDGKGITRNFSTCSPSTKTCPDGHCDVVETQDINICPQDCLRGSIVGGHEPGEPRGIKAGYGTCNCFPEEEKCFCEPEDIQDPLCDELCRTVIAAAVLFSFIVSVLLSAFCIHCYHKFAHKPPISSAEMTFRRPAQAFPVSYSSSGARRPSLDSMENQVSVDAFKILEDPKWEFPRKNLVLGKTLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVFADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRADGTNTGFPRYPNDSVYANWMLSPSAAKLMDTFDS

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
5	Phosphorylation	---MAKATSGAAGLR ---CCCCCCHHHHHH	27.30	25022875
6	Phosphorylation	--MAKATSGAAGLRL --CCCCCCHHHHHHH	31.15	25022875
30	Phosphorylation	GKVALGLYFSRDAYW HHHHHHHHHCCHHHH	9.56	25022875
32	Phosphorylation	VALGLYFSRDAYWEK HHHHHHHCCHHHHHH	18.72	25022875
98	N-linked_Glycosylation	DTGLLYLNRSLDHSS CCCEEEEECCCCCCC	20.24	UniProtKB CARBOHYD
108 (in isoform 2)	Ubiquitination	-	39.54	-
108	Ubiquitination	LDHSSWEKLSVRNRG CCCCCCHHHCCCCCC	39.54	-
151	N-linked_Glycosylation	RVYFSFFNTSFPACS EEEEEECCCCCCCHH	32.57	20473317
159	Phosphorylation	TSFPACSSLKPRELC CCCCCHHCCCHHHHC	40.05	-
199	N-linked_Glycosylation	PVQFLCPNISVAYRL EHHHHCCCEEHHHHH	37.86	UniProtKB CARBOHYD
201	Phosphorylation	QFLCPNISVAYRLLE HHHCCCEEHHHHHHC	13.82	22210691
336	N-linked_Glycosylation	FRVEHWPNETSVQAN EEEECCCCCCCEEEC	61.05	UniProtKB CARBOHYD
343	N-linked_Glycosylation	NETSVQANGSFVRAT CCCCEEECCCEEEEE	29.56	UniProtKB CARBOHYD
350	Phosphorylation	NGSFVRATVHDYRLV CCCEEEEEEEEEEEH	14.07	27251275
361	N-linked_Glycosylation	YRLVLNRNLSISENR EEEHHCCCCCCCCCC	36.75	UniProtKB CARBOHYD
367	N-linked_Glycosylation	RNLSISENRTMQLAV CCCCCCCCCEEEEEE	37.62	UniProtKB CARBOHYD
377	N-linked_Glycosylation	MQLAVLVNDSDFQGP EEEEEEECCCCCCCC	38.62	UniProtKB CARBOHYD
394	N-linked_Glycosylation	GVLLLHFNVSVLPVS EEEEEEEEEEEEEEE	17.88	UniProtKB CARBOHYD
411	Phosphorylation	LPSTYSLSVSRRARR CCCCCCCCHHHHHHH	16.47	24719451
448	N-linked_Glycosylation	KLHSSGANCSTLGVV EEECCCCCCCEEEEE	24.65	UniProtKB CARBOHYD
468	N-linked_Glycosylation	TSGILFVNDTKALRR CCCEEEECCCCHHCC	43.85	UniProtKB CARBOHYD
536	Phosphorylation	EECGGLGSPTGRCEW CCCCCCCCCCCCEEE	25.08	23403867
538	Phosphorylation	CGGLGSPTGRCEWRQ CCCCCCCCCCEEEEC	38.67	23403867
554	N-linked_Glycosylation	DGKGITRNFSTCSPS CCCCCCCCEECCCCC	26.94	UniProtKB CARBOHYD
675	Phosphorylation	PISSAEMTFRRPAQA CCCCCEEEECCCHHH	12.90	22128160
686	Phosphorylation	PAQAFPVSYSSSGAR CHHHCCCCCCCCCCC	21.38	25884760
687	Phosphorylation	AQAFPVSYSSSGARR HHHCCCCCCCCCCCC	16.89	28348404
688	Phosphorylation	QAFPVSYSSSGARRP HHCCCCCCCCCCCCC	15.55	25884760
689	Phosphorylation	AFPVSYSSSGARRPS HCCCCCCCCCCCCCC	25.26	28152594
690	Phosphorylation	FPVSYSSSGARRPSL CCCCCCCCCCCCCCH	30.45	28152594
696	Phosphorylation	SSGARRPSLDSMENQ CCCCCCCCHHHHCCC	42.89	19369195
699	Phosphorylation	ARRPSLDSMENQVSV CCCCCHHHHCCCCCH	33.03	28450419
705	Phosphorylation	DSMENQVSVDAFKIL HHHCCCCCHHHHHHH	12.43	27732954
752	Phosphorylation	HLKGRAGYTTVAVKM EECCCCCCHHHHHHH	9.76	20068231
753	Phosphorylation	LKGRAGYTTVAVKML ECCCCCCHHHHHHHH	17.55	20068231
754	Phosphorylation	KGRAGYTTVAVKMLK CCCCCCHHHHHHHHH	9.66	20068231
791	Phosphorylation	HPHVIKLYGACSQDG CCCHHEEEEEECCCC	9.55	15753368
806	Phosphorylation	PLLLIVEYAKYGSLR CEEEEEEHHHHCCHH	9.48	14711813
809	Phosphorylation	LIVEYAKYGSLRGFL EEEEHHHHCCHHHHH	12.08	14711813
826	Phosphorylation	SRKVGPGYLGSGGSR CCCCCCCCCCCCCCC	15.83	19060924
864	Phosphorylation	QISQGMQYLAEMKLV HHHHHHHHHHHCCHH	10.05	8637703
891	Phosphorylation	EGRKMKISDFGLSRD CCCCEEHHHCCCCCC	22.74	15753368
900	Phosphorylation	FGLSRDVYEEDSYVK CCCCCCCCCCCHHCC	20.21	25884760
904	Phosphorylation	RDVYEEDSYVKRSQG CCCCCCCHHCCCCCC	34.80	27642862
905	Phosphorylation	DVYEEDSYVKRSQGR CCCCCCHHCCCCCCC	23.47	11956105
907 (in isoform 2)	Ubiquitination	-	37.79	-
907	Ubiquitination	YEEDSYVKRSQGRIP CCCCHHCCCCCCCCC	37.79	-
909	Phosphorylation	EDSYVKRSQGRIPVK CCHHCCCCCCCCCCC	31.13	-
928	Phosphorylation	ESLFDHIYTTQSDVW HHHHHHCCCCHHHHH	10.58	11956105
952	Phosphorylation	VTLGGNPYPGIPPER HHCCCCCCCCCCHHH	20.35	11956105
981	Phosphorylation	DNCSEEMYRLMLQCW CCCCHHHHHHHHHHH	12.13	14711813
1015	Phosphorylation	MMVKRRDYLDLAAST HHHHCHHHHHHHCCC	10.58	19060924
1029	Phosphorylation	TPSDSLIYDDGLSEE CCCCCEECCCCCCCC	17.18	19060924
1034	Phosphorylation	LIYDDGLSEEETPLV EECCCCCCCCCCCCC	48.79	28348404
1038	Phosphorylation	DGLSEEETPLVDCNN CCCCCCCCCCCCCCC	25.79	28348404
1060	Ubiquitination	PSTWIENKLYGMSDP CCCHHHCCCCCCCCC	30.23	-
1062	Phosphorylation	TWIENKLYGMSDPNW CHHHCCCCCCCCCCC	16.64	19060924
1062 (in isoform 2)	Phosphorylation	-	16.64	14711813
1065	Phosphorylation	ENKLYGMSDPNWPGE HCCCCCCCCCCCCCC	45.62	-
1090	Phosphorylation	TNTGFPRYPNDSVYA CCCCCCCCCCCCHHH	13.46	14711813
1094	Phosphorylation	FPRYPNDSVYANWML CCCCCCCCHHHCCCC	24.54	26356563
1096	Phosphorylation	RYPNDSVYANWMLSP CCCCCCHHHCCCCCH	9.73	7845675
1107	Ubiquitination	MLSPSAAKLMDTFDS CCCHHHHHHHHHCCC	44.02	-
1111	Phosphorylation	SAAKLMDTFDS---- HHHHHHHHCCC----	18.51	23836654
1114	Phosphorylation	KLMDTFDS------- HHHHHCCC-------	37.62	23836654

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
675	T	Phosphorylation	Kinase	PRKCA	P17252	GPS
687	Y	Phosphorylation	Kinase	RET	P07949	PSP
696	S	Phosphorylation	Kinase	PRKACA	P17612	GPS
696	S	Phosphorylation	Kinase	PKA-FAMILY	-	GPS
806	Y	Phosphorylation	Kinase	RET	P07949	PSP
809	Y	Phosphorylation	Kinase	RET	P07949	PSP
826	Y	Phosphorylation	Kinase	RET	P07949	PSP
900	Y	Phosphorylation	Kinase	RET	P07949	PSP
905	Y	Phosphorylation	Kinase	RET	P07949	PSP
905	Y	Phosphorylation	Kinase	SRC	P12931	PSP
905	Y	Phosphorylation	Kinase	SRC	P05480	PSP
905	Y	Phosphorylation	Kinase	PTK2	Q05397	GPS
981	Y	Phosphorylation	Kinase	RET	P07949	PSP
1015	Y	Phosphorylation	Kinase	RET	P07949	PSP
1029	Y	Phosphorylation	Kinase	RET	P07949	PSP
1062	Y	Phosphorylation	Kinase	RET	P07949	PSP
1062	Y	Phosphorylation	Kinase	RET	P35546	PSP
1090	Y	Phosphorylation	Kinase	RET	P07949	PSP
1096	Y	Phosphorylation	Kinase	RET	P07949	PSP

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
Oops, there are no descriptions of PTM sites of RET_HUMAN !!

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 RET_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
STAT3_HUMAN	STAT3	physical	15485908
STAT3_HUMAN	STAT3	physical	12637586
DOK5_HUMAN	DOK5	physical	11470823
DOK1_HUMAN	DOK1	physical	12087092
GRB7_HUMAN	GRB7	physical	8631863
NRTN_HUMAN	NRTN	physical	9192898
GFRA1_HUMAN	GFRA1	physical	9192898
GFRA1_HUMAN	GFRA1	physical	10829012
GRB10_HUMAN	GRB10	physical	7665556
STAT3_HUMAN	STAT3	physical	11536047
CBL_HUMAN	CBL	physical	12727845
CBLC_HUMAN	CBLC	physical	18753381
RET_HUMAN	RET	physical	12787916
PDLI7_HUMAN	PDLIM7	physical	24466333
CBLC_HUMAN	CBLC	physical	24466333
NT2NL_HUMAN	NOTCH2NL	physical	25416956
AIP_HUMAN	AIP	physical	19366855
TZAP_HUMAN	ZBTB48	physical	26496610
H31_HUMAN	HIST1H3A	physical	26496610
KYNU_HUMAN	KYNU	physical	26496610
TXN4A_HUMAN	TXNL4A	physical	26496610
ZCHC8_HUMAN	ZCCHC8	physical	26496610
ICE2_HUMAN	ICE2	physical	26496610
PLCG1_HUMAN	PLCG1	physical	25241761
STAT3_HUMAN	STAT3	physical	25241761
MK01_HUMAN	MAPK1	physical	25241761
PTPRR_HUMAN	PTPRR	physical	28065597
DUS26_HUMAN	DUSP26	physical	28065597

Drug and Disease Associations

Kegg Disease
H00032	Thyroid cancer
H00822	Renal agenesis and Renal adysplasia
H00910	Hirschsprung disease (HD)
H00916	Congenital central hypoventilation syndrome (CCHS)
OMIM Disease
114500	Colorectal cancer (CRC)
142623	Hirschsprung disease 1 (HSCR1)
155240	Medullary thyroid carcinoma (MTC)
162300	Multiple neoplasia 2B (MEN2B)
171300	Pheochromocytoma (PCC)
171400	Multiple neoplasia 2A (MEN2A)
188550	Thyroid papillary carcinoma (TPC)
	Note=Mutations in RET have been detected in patients with renal agenesis suggesting a possible involvement of this gene in disease pathogenesis.
209880
Kegg Drug
D06402	Sunitinib malate (JAN/USAN); Sutent (TN)
D06678	Motesanib; AMG 706
D08552	Sunitinib (INN)
D08947	Motesanib phosphate (JAN); Motesanib diphosphate (USAN)
D10062	Cabozantinib (USAN)
D10095	Cabozantinib s-malate (USAN); Cometriq (TN)
DrugBank
There are no disease associations of PTM sites.

Regulatory Network of RET_HUMAN

Related Literatures of Post-Translational Modification

N-linked Glycosylation
Reference	PubMed
"Mammal-restricted elements predispose human RET to folding impairmentby HSCR mutations."; Kjaer S., Hanrahan S., Totty N., McDonald N.Q.; Nat. Struct. Mol. Biol. 17:726-731(2010). Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 29-270, GLYCOSYLATION ATASN-151, AND DISULFIDE BOND.	20473317 [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-696, AND MASSSPECTROMETRY.	19369195 [Abstract]
"Synthesis, structure-activity relationship and crystallographicstudies of 3-substituted indolin-2-one RET inhibitors."; Mologni L., Rostagno R., Brussolo S., Knowles P.P., Kjaer S.,Murray-Rust J., Rosso E., Zambon A., Scapozza L., McDonald N.Q.,Lucchini V., Gambacorti-Passerini C.; Bioorg. Med. Chem. 18:1482-1496(2010). Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 705-1013 IN COMPLEX WITHINHIBITORS, ENZYME REGULATION, AND PHOSPHORYLATION AT TYR-905.	20117004 [Abstract]
"Structure and chemical inhibition of the RET tyrosine kinasedomain."; Knowles P.P., Murray-Rust J., Kjaer S., Scott R.P., Hanrahan S.,Santoro M., Ibanez C.F., McDonald N.Q.; J. Biol. Chem. 281:33577-33587(2006). Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 705-1013 ALONE AND IN COMPLEXWITH INHIBITORS, MASS SPECTROMETRY, AND PHOSPHORYLATION AT TYR-900 ANDTYR-905.	16928683 [Abstract]
"The receptor-type protein tyrosine phosphatase J antagonizes thebiochemical and biological effects of RET-derived oncoproteins."; Iervolino A., Iuliano R., Trapasso F., Viglietto G., Melillo R.M.,Carlomagno F., Santoro M., Fusco A.; Cancer Res. 66:6280-6287(2006). Cited for: AUTOPHOSPHORYLATION AT TYR-905; TYR-1015 AND TYR-1062, ANDDEPHOSPHORYLATION BY PTPRJ AT TYR-905; TYR-1015 AND TYR-1062.	16778204 [Abstract]
"Identification of RET autophosphorylation sites by massspectrometry."; Kawamoto Y., Takeda K., Okuno Y., Yamakawa Y., Ito Y., Taguchi R.,Kato M., Suzuki H., Takahashi M., Nakashima I.; J. Biol. Chem. 279:14213-14224(2004). Cited for: PHOSPHORYLATION AT TYR-806; TYR-809; TYR-900; TYR-905; TYR-981;TYR-1015; TYR-1062; TYR-1090 AND TYR-1096.	14711813 [Abstract]
"Tyrosines 1015 and 1062 are in vivo autophosphorylation sites in retand ret-derived oncoproteins."; Salvatore D., Barone M.V., Salvatore G., Melillo R.M., Chiappetta G.,Mineo A., Fenzi G., Vecchio G., Fusco A., Santoro M.; J. Clin. Endocrinol. Metab. 85:3898-3907(2000). Cited for: PHOSPHORYLATION AT TYR-1015 AND TYR-1062.	11061555 [Abstract]