dbPTM

SIK1_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	SIK1_HUMAN
UniProt AC	P57059
Protein Name	Serine/threonine-protein kinase SIK1
Gene Name	SIK1
Organism	Homo sapiens (Human).
Sequence Length	783
Subcellular Localization	Cytoplasm . Nucleus . Following ACTH (adrenocorticotropic hormone) treatment and subsequent phosphorylation by PKA, translocates to the cytoplasm, where it binds to YWHAZ.
Protein Description	Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression. Phosphorylates HDAC4, HDAC5, PPME1, SREBF1, CRTC1/TORC1 and CRTC2/TORC2. Acts as a tumor suppressor and plays a key role in p53/TP53-dependent anoikis, a type of apoptosis triggered by cell detachment: required for phosphorylation of p53/TP53 in response to loss of adhesion and is able to suppress metastasis. Part of a sodium-sensing signaling network, probably by mediating phosphorylation of PPME1: following increases in intracellular sodium, SIK1 is activated by CaMK1 and phosphorylates PPME1 subunit of protein phosphatase 2A (PP2A), leading to dephosphorylation of sodium/potassium-transporting ATPase ATP1A1 and subsequent increase activity of ATP1A1. Acts as a regulator of muscle cells by phosphorylating and inhibiting class II histone deacetylases HDAC4 and HDAC5, leading to promote expression of MEF2 target genes in myocytes. Also required during cardiomyogenesis by regulating the exit of cardiomyoblasts from the cell cycle via down-regulation of CDKN1C/p57Kip2. Acts as a regulator of hepatic gluconeogenesis by phosphorylating and repressing the CREB-specific coactivators CRTC1/TORC1 and CRTC2/TORC2, leading to inhibit CREB activity. Also regulates hepatic lipogenesis by phosphorylating and inhibiting SREBF1. In concert with CRTC1/TORC1, regulates the light-induced entrainment of the circadian clock by attenuating PER1 induction; represses CREB-mediated transcription of PER1 by phosphorylating and deactivating CRTC1/TORC1 (By similarity)..
Protein Sequence	MVIMSEFSADPAGQGQGQQKPLRVGFYDIERTLGKGNFAVVKLARHRVTKTQVAIKIIDKTRLDSSNLEKIYREVQLMKLLNHPHIIKLYQVMETKDMLYIVTEFAKNGEMFDYLTSNGHLSENEARKKFWQILSAVEYCHDHHIVHRDLKTENLLLDGNMDIKLADFGFGNFYKSGEPLSTWCGSPPYAAPEVFEGKEYEGPQLDIWSLGVVLYVLVCGSLPFDGPNLPTLRQRVLEGRFRIPFFMSQDCESLIRRMLVVDPARRITIAQIRQHRWMRAEPCLPGPACPAFSAHSYTSNLGDYDEQALGIMQTLGVDRQRTVESLQNSSYNHFAAIYYLLLERLKEYRNAQCARPGPARQPRPRSSDLSGLEVPQEGLSTDPFRPALLCPQPQTLVQSVLQAEMDCELQSSLQWPLFFPVDASCSGVFRPRPVSPSSLLDTAISEEARQGPGLEEEQDTQESLPSSTGRRHTLAEVSTRLSPLTAPCIVVSPSTTASPAEGTSSDSCLTFSASKSPAGLSGTPATQGLLGACSPVRLASPFLGSQSATPVLQAQGGLGGAVLLPVSFQEGRRASDTSLTQGLKAFRQQLRKTTRTKGFLGLNKIKGLARQVCQAPASRASRGGLSPFHAPAQSPGLHGGAAGSREGWSLLEEVLEQQRLLQLQHHPAAAPGCSQAPQPAPAPFVIAPCDGPGAAPLPSTLLTSGLPLLPPPLLQTGASPVASAAQLLDTHLHIGTGPTALPAVPPPRLARLAPGCEPLGLLQGDCEMEDLMPCSLGTFVLVQ

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
20	Sumoylation	GQGQGQQKPLRVGFY CCCCCCCCCEEEEEE	37.82	-
20	Ubiquitination	GQGQGQQKPLRVGFY CCCCCCCCCEEEEEE	37.82	29967540
20	Sumoylation	GQGQGQQKPLRVGFY CCCCCCCCCEEEEEE	37.82	-
32	Phosphorylation	GFYDIERTLGKGNFA EEEEHHCCCCCCCEE	27.37	24719451
35	Ubiquitination	DIERTLGKGNFAVVK EHHCCCCCCCEEEEE	54.52	21963094
42	Ubiquitination	KGNFAVVKLARHRVT CCCEEEEEHHHCCCC	29.81	21963094
49	Phosphorylation	KLARHRVTKTQVAIK EHHHCCCCCEEHHEE	28.47	29888752
50	Ubiquitination	LARHRVTKTQVAIKI HHHCCCCCEEHHEEE	33.82	21963094
51	Phosphorylation	ARHRVTKTQVAIKII HHCCCCCEEHHEEEE	20.93	29888752
56	Ubiquitination	TKTQVAIKIIDKTRL CCEEHHEEEEECCCC	24.70	29967540
60	Ubiquitination	VAIKIIDKTRLDSSN HHEEEEECCCCCCCH	25.74	29967540
70	Ubiquitination	LDSSNLEKIYREVQL CCCCHHHHHHHHHHH	48.48	29967540
88	Ubiquitination	LNHPHIIKLYQVMET HCCHHHHHHEEHHHH	40.30	21963094
151	Ubiquitination	HIVHRDLKTENLLLD CCCCCCCCCCCEEEC	59.07	21963094
164	Ubiquitination	LDGNMDIKLADFGFG ECCCCCEEEECCCCC	33.10	21987572
175	Sumoylation	FGFGNFYKSGEPLST CCCCCCCCCCCCCHH	48.09	-
175	Ubiquitination	FGFGNFYKSGEPLST CCCCCCCCCCCCCHH	48.09	21963094
181	Phosphorylation	YKSGEPLSTWCGSPP CCCCCCCHHCCCCCC	30.49	27251275
182	Phosphorylation	KSGEPLSTWCGSPPY CCCCCCHHCCCCCCC	32.24	14976552
186	Phosphorylation	PLSTWCGSPPYAAPE CCHHCCCCCCCCCCH	21.40	25159151
322	Phosphorylation	LGVDRQRTVESLQNS HCCCCHHHHHHHHCC	21.93	-
366	Phosphorylation	ARQPRPRSSDLSGLE CCCCCCCCCCCCCCC	30.77	20071362
370	Phosphorylation	RPRSSDLSGLEVPQE CCCCCCCCCCCCCCC	46.45	20071362
435	Phosphorylation	VFRPRPVSPSSLLDT CCCCCCCCHHHHHHH	23.03	29255136
437	Phosphorylation	RPRPVSPSSLLDTAI CCCCCCHHHHHHHHH	26.55	23663014
438	Phosphorylation	PRPVSPSSLLDTAIS CCCCCHHHHHHHHHC	36.01	30108239
460	Phosphorylation	GLEEEQDTQESLPSS CCCCCHHCHHCCCCC	33.65	17525332
473	Phosphorylation	SSTGRRHTLAEVSTR CCCCCCCCHHHHHHC	26.33	26657352
479	Phosphorylation	HTLAEVSTRLSPLTA CCHHHHHHCCCCCCC	40.58	17525332
492	Phosphorylation	TAPCIVVSPSTTASP CCCEEEECCCCCCCC	11.39	28348404
494	Phosphorylation	PCIVVSPSTTASPAE CEEEECCCCCCCCCC	30.77	28348404
495	Phosphorylation	CIVVSPSTTASPAEG EEEECCCCCCCCCCC	29.75	28348404
496	Phosphorylation	IVVSPSTTASPAEGT EEECCCCCCCCCCCC	29.49	28348404
498	Phosphorylation	VSPSTTASPAEGTSS ECCCCCCCCCCCCCC	23.66	28348404
503	Phosphorylation	TASPAEGTSSDSCLT CCCCCCCCCCCCEEE	19.30	28348404
504	Phosphorylation	ASPAEGTSSDSCLTF CCCCCCCCCCCEEEE	42.90	28348404
505	Phosphorylation	SPAEGTSSDSCLTFS CCCCCCCCCCEEEEE	33.12	28348404
507	Phosphorylation	AEGTSSDSCLTFSAS CCCCCCCCEEEEECC	16.99	28348404
516	Phosphorylation	LTFSASKSPAGLSGT EEEECCCCCCCCCCC	19.93	25159151
534	Phosphorylation	QGLLGACSPVRLASP CHHHCCCCCCCCCCC	26.37	28985074
535	Ubiquitination	GLLGACSPVRLASPF HHHCCCCCCCCCCCC	18.35	21963094
543	Ubiquitination	VRLASPFLGSQSATP CCCCCCCCCCCCCCH	7.97	22817900
545	Phosphorylation	LASPFLGSQSATPVL CCCCCCCCCCCCHHC	24.10	28348404
547	Phosphorylation	SPFLGSQSATPVLQA CCCCCCCCCCHHCCC	35.49	28348404
548	Ubiquitination	PFLGSQSATPVLQAQ CCCCCCCCCHHCCCC	14.32	21963094
549	Phosphorylation	FLGSQSATPVLQAQG CCCCCCCCHHCCCCC	21.12	28348404
555	Ubiquitination	ATPVLQAQGGLGGAV CCHHCCCCCCCCCEE	33.26	21963094
557	Ubiquitination	PVLQAQGGLGGAVLL HHCCCCCCCCCEEEE	14.74	22817900
575	Phosphorylation	FQEGRRASDTSLTQG CCCCCCCCCCCHHHH	39.34	25159151
577	Phosphorylation	EGRRASDTSLTQGLK CCCCCCCCCHHHHHH	24.12	21815630
578	Phosphorylation	GRRASDTSLTQGLKA CCCCCCCCHHHHHHH	34.12	20873877
580	Phosphorylation	RASDTSLTQGLKAFR CCCCCCHHHHHHHHH	21.99	23927012
584	Sumoylation	TSLTQGLKAFRQQLR CCHHHHHHHHHHHHH	52.91	-
584	Ubiquitination	TSLTQGLKAFRQQLR CCHHHHHHHHHHHHH	52.91	21963094
584	Sumoylation	TSLTQGLKAFRQQLR CCHHHHHHHHHHHHH	52.91	-
592	Ubiquitination	AFRQQLRKTTRTKGF HHHHHHHHHHCCCCC	63.94	22817900
597	Ubiquitination	LRKTTRTKGFLGLNK HHHHHCCCCCCCHHH	44.36	21963094
604	Sumoylation	KGFLGLNKIKGLARQ CCCCCHHHHHHHHHH	51.33	-
604	Ubiquitination	KGFLGLNKIKGLARQ CCCCCHHHHHHHHHH	51.33	21963094
604	Sumoylation	KGFLGLNKIKGLARQ CCCCCHHHHHHHHHH	51.33	-
606	Ubiquitination	FLGLNKIKGLARQVC CCCHHHHHHHHHHHH	49.86	22817900
626	Phosphorylation	RASRGGLSPFHAPAQ HHHCCCCCCCCCCCC	28.88	30576142
634	Phosphorylation	PFHAPAQSPGLHGGA CCCCCCCCCCCCCCC	24.04	33259812
644	Phosphorylation	LHGGAAGSREGWSLL CCCCCCCCHHHHHHH	23.56	20071362

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
182	T	Phosphorylation	Kinase	GSK3B	P49841	GPS
182	T	Phosphorylation	Kinase	STK11	Q15831	PhosphoELM
186	S	Phosphorylation	Kinase	SIK1	P57059	GPS
322	T	Phosphorylation	Kinase	CAMK1	Q14012	Uniprot
473	T	Phosphorylation	Kinase	PKA	-	Uniprot
575	S	Phosphorylation	Kinase	PKA	-	Uniprot

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
182	T	Phosphorylation	14976552
Autophosphorylation at Ser-186 is maintained by sequential phosphorylation at Thr-182 by GSK3-beta.
182	T	Phosphorylation	14976552
GSK3-beta cannot initiate phosphorylation at Thr-182, it can only maintain it.
182	T	Phosphorylation	14976552
Phosphorylated at Thr-182 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39, leading to its activation.
182	T	Phosphorylation	14976552
Phosphorylation at Thr-182 promotes autophosphorylation at Ser-186, which is required for sustained activity.
186	S	Phosphorylation	18348280
Autophosphorylation at Ser-186 is maintained by sequential phosphorylation at Thr-182 by GSK3-beta.
186	S	Phosphorylation	18348280
Phosphorylation at Thr-182 promotes autophosphorylation at Ser-186, which is required for sustained activity.
322	T	Phosphorylation	18348280
Phosphorylation at Thr-322 by CaMK1 following intracellular sodium concentration leads to activation.
575	S	Phosphorylation	29211348
Phosphorylation at Ser-575 in response to cAMP signaling promotes translocation to the cytoplasm.

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 SIK1_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
HDAC5_HUMAN	HDAC5	physical	23256157
SPT5H_HUMAN	SUPT5H	physical	21988832
TAB2_HUMAN	TAB2	physical	24061540
M3K7_HUMAN	MAP3K7	physical	24061540
RING2_HUMAN	RNF2	physical	27911266
PSF2_HUMAN	GINS2	physical	28514442
SIK2_HUMAN	SIK2	physical	28514442
SLD5_HUMAN	GINS4	physical	28514442
UB2E1_HUMAN	UBE2E1	physical	28514442
SIK3_HUMAN	SIK3	physical	28514442

Drug and Disease Associations

Kegg Disease
There are no disease associations of PTM sites.
OMIM Disease
616341	Epileptic encephalopathy, early infantile, 30 (EIEE30)
Kegg Drug
There are no disease associations of PTM sites.
DrugBank
DB08912	Dabrafenib

Regulatory Network of SIK1_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-435 AND SER-575, ANDMASS SPECTROMETRY.	19369195 [Abstract]
"Importance of autophosphorylation at Ser186 in the A-loop of saltinducible kinase 1 for its sustained kinase activity."; Hashimoto Y.K., Satoh T., Okamoto M., Takemori H.; J. Cell. Biochem. 104:1724-1739(2008). Cited for: FUNCTION, AUTOPHOSPHORYLATION, PHOSPHORYLATION AT THR-182 AND SER-186,INTERACTION WITH YWHAZ, AND MUTAGENESIS OF LYS-56; SER-135; SER-186;SER-209 AND SER-248.	18348280 [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 THR-460 AND THR-479, ANDMASS SPECTROMETRY.	17525332 [Abstract]
"LKB1 is a master kinase that activates 13 kinases of the AMPKsubfamily, including MARK/PAR-1."; Lizcano J.M., Goeransson O., Toth R., Deak M., Morrice N.A.,Boudeau J., Hawley S.A., Udd L., Maekelae T.P., Hardie D.G.,Alessi D.R.; EMBO J. 23:833-843(2004). Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, ENZYME REGULATION,PHOSPHORYLATION AT THR-182, AND MUTAGENESIS OF THR-182.	14976552 [Abstract]

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