P57059 · SIK1_HUMAN
- ProteinSerine/threonine-protein kinase SIK1
- GeneSIK1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids783 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
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. Inhibits CREB activity by phosphorylating and inhibiting activity of TORCs, the CREB-specific coactivators, like CRTC2/TORC2 and CRTC3/TORC3 in response to cAMP signaling (PubMed:29211348).
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).
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).
Catalytic activity
- ATP + L-seryl-[protein] = ADP + H+ + O-phospho-L-seryl-[protein]
Cofactor
Activity regulation
Activated by phosphorylation on Thr-182 (PubMed:14976552).
Also activated by phosphorylation on Thr-322 in response to increases in intracellular sodium in parallel with elevations in intracellular calcium through the reversible sodium/calcium exchanger (PubMed:14976552).
Inhibited by phosphorylation at Thr-473 and Ser-575, probably by PKA, which triggers interaction with 14-3-3 proteins (PubMed:29211348).
Also activated by phosphorylation on Thr-322 in response to increases in intracellular sodium in parallel with elevations in intracellular calcium through the reversible sodium/calcium exchanger (PubMed:14976552).
Inhibited by phosphorylation at Thr-473 and Ser-575, probably by PKA, which triggers interaction with 14-3-3 proteins (PubMed:29211348).
Features
Showing features for binding site, active site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameSerine/threonine-protein kinase SIK1
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP57059
- Secondary accessions
Proteomes
Organism-specific databases
Disease & Variants
Involvement in disease
Developmental and epileptic encephalopathy 30 (DEE30)
- Note
- DescriptionA form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent.
- See alsoMIM:616341
Natural variants in DEE30
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_073701 | 287 | P>T | in DEE30; no change in subcellular location; dbSNP:rs786205159 | |
VAR_073702 | 411 | S>C | in DEE30; no change in subcellular location | |
VAR_073703 | 636 | G>S | in DEE30; no change in subcellular location; dbSNP:rs786205163 |
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_041087 | 15 | in dbSNP:rs3746951 | |||
Sequence: G → S | ||||||
Mutagenesis | 56 | Loss of kinase activity. | ||||
Sequence: K → M | ||||||
Mutagenesis | 135 | Decreased kinase activity without affecting much autophosphorylation status. | ||||
Sequence: S → A | ||||||
Natural variant | VAR_041088 | 142 | in dbSNP:rs45491503 | |||
Sequence: D → N | ||||||
Mutagenesis | 182 | Prevents phosphorylation and activation by STK11/LKB1 complex. Reduced inhibition of CRTC3-mediated transcriptional activity. | ||||
Sequence: T → A | ||||||
Mutagenesis | 186 | Impaired autophosphorylation and kinase activity. | ||||
Sequence: S → A, D, C, or G | ||||||
Mutagenesis | 186 | Does not autophosphorylation and kinase activity. | ||||
Sequence: S → T | ||||||
Mutagenesis | 209 | Decreased kinase activity without affecting much autophosphorylation status. | ||||
Sequence: S → A | ||||||
Natural variant | VAR_041089 | 211 | in a glioblastoma multiforme sample; somatic mutation | |||
Sequence: G → S | ||||||
Mutagenesis | 248 | Decreased kinase activity without affecting much autophosphorylation status. | ||||
Sequence: S → A | ||||||
Natural variant | VAR_073701 | 287 | in DEE30; no change in subcellular location; dbSNP:rs786205159 | |||
Sequence: P → T | ||||||
Natural variant | VAR_073702 | 411 | in DEE30; no change in subcellular location | |||
Sequence: S → C | ||||||
Natural variant | VAR_033910 | 430 | in dbSNP:rs34164089 | |||
Sequence: R → W | ||||||
Natural variant | VAR_041090 | 469 | in a metastatic melanoma sample; somatic mutation | |||
Sequence: G → D | ||||||
Mutagenesis | 473 | Reduced but still present interaction with 14-3-3 proteins in response to cAMP signaling and, thus, still able to inhibit TORC activity. Resistant to inhibition by cAMP signaling and, thus, still able to inhibit TORC activity; when associated with A-575. | ||||
Sequence: T → A | ||||||
Mutagenesis | 473 | Reduced but still present interaction with 14-3-3 proteins in response to cAMP signaling and, thus, still able to inhibit TORC activity. | ||||
Sequence: T → E | ||||||
Mutagenesis | 575 | Loss of interaction with 14-3-3 proteins in response to cAMP signaling and, thus, still able to inhibit TORC activity. Resistant to inhibition by cAMP signaling and, thus, still able to inhibit TORC activity; when associated with A-473. | ||||
Sequence: S → A | ||||||
Mutagenesis | 575 | Strongly reduced but still present interaction with 14-3-3 proteins in response to cAMP signaling and, thus, still able to inhibit TORC activity. | ||||
Sequence: S → E | ||||||
Natural variant | VAR_021255 | 615 | in dbSNP:rs430554 | |||
Sequence: A → V | ||||||
Natural variant | VAR_073703 | 636 | in DEE30; no change in subcellular location; dbSNP:rs786205163 | |||
Sequence: G → S | ||||||
Natural variant | VAR_041091 | 696 | in dbSNP:rs56386767 | |||
Sequence: P → L | ||||||
Natural variant | VAR_041092 | 725 | in dbSNP:rs35596465 | |||
Sequence: A → V |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 733 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000086659 | 1-783 | UniProt | Serine/threonine-protein kinase SIK1 | |||
Sequence: MVIMSEFSADPAGQGQGQQKPLRVGFYDIERTLGKGNFAVVKLARHRVTKTQVAIKIIDKTRLDSSNLEKIYREVQLMKLLNHPHIIKLYQVMETKDMLYIVTEFAKNGEMFDYLTSNGHLSENEARKKFWQILSAVEYCHDHHIVHRDLKTENLLLDGNMDIKLADFGFGNFYKSGEPLSTWCGSPPYAAPEVFEGKEYEGPQLDIWSLGVVLYVLVCGSLPFDGPNLPTLRQRVLEGRFRIPFFMSQDCESLIRRMLVVDPARRITIAQIRQHRWMRAEPCLPGPACPAFSAHSYTSNLGDYDEQALGIMQTLGVDRQRTVESLQNSSYNHFAAIYYLLLERLKEYRNAQCARPGPARQPRPRSSDLSGLEVPQEGLSTDPFRPALLCPQPQTLVQSVLQAEMDCELQSSLQWPLFFPVDASCSGVFRPRPVSPSSLLDTAISEEARQGPGLEEEQDTQESLPSSTGRRHTLAEVSTRLSPLTAPCIVVSPSTTASPAEGTSSDSCLTFSASKSPAGLSGTPATQGLLGACSPVRLASPFLGSQSATPVLQAQGGLGGAVLLPVSFQEGRRASDTSLTQGLKAFRQQLRKTTRTKGFLGLNKIKGLARQVCQAPASRASRGGLSPFHAPAQSPGLHGGAAGSREGWSLLEEVLEQQRLLQLQHHPAAAPGCSQAPQPAPAPFVIAPCDGPGAAPLPSTLLTSGLPLLPPPLLQTGASPVASAAQLLDTHLHIGTGPTALPAVPPPRLARLAPGCEPLGLLQGDCEMEDLMPCSLGTFVLVQ | |||||||
Modified residue | 182 | UniProt | Phosphothreonine; by LKB1 and GSK3-beta | ||||
Sequence: T | |||||||
Modified residue | 186 | UniProt | Phosphoserine; by autocatalysis | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 186 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 322 | UniProt | Phosphothreonine; by CaMK1 | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 435 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 437 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 438 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 473 | UniProt | Phosphothreonine; by PKA | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 473 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 516 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 534 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 575 | UniProt | Phosphoserine; by PKA | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 575 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 626 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 634 | PRIDE | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Phosphorylated at Thr-182 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39, leading to its activation. Phosphorylation at Thr-182 promotes autophosphorylation at Ser-186, which is required for sustained activity. Autophosphorylation at Ser-186 is maintained by sequential phosphorylation at Thr-182 by GSK3-beta. GSK3-beta cannot initiate phosphorylation at Thr-182, it can only maintain it. Phosphorylation at Ser-575 in response to cAMP signaling promotes translocation to the cytoplasm (PubMed:29211348).
Phosphorylation at Thr-322 by CaMK1 following intracellular sodium concentration leads to activation
Phosphorylation at Thr-322 by CaMK1 following intracellular sodium concentration leads to activation
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Interaction
Subunit
Interacts with ATP1A1 (By similarity).
Interacts (when phosphorylated on Thr-182 and Ser-186) with YWHAZ (PubMed:16306228).
Interacts (when phosphorylated at Thr-473 and/or Ser-575) with 14-3-3 proteins; the interaction inhibits kinase activity towards TORCs (PubMed:29211348).
There is a cooperative effect of the phosphorylation sites in 14-3-3 binding as the interaction is stronger when both Thr-473 and Ser-575 are modified (PubMed:29211348).
Interacts (when phosphorylated on Thr-182 and Ser-186) with YWHAZ (PubMed:16306228).
Interacts (when phosphorylated at Thr-473 and/or Ser-575) with 14-3-3 proteins; the interaction inhibits kinase activity towards TORCs (PubMed:29211348).
There is a cooperative effect of the phosphorylation sites in 14-3-3 binding as the interaction is stronger when both Thr-473 and Ser-575 are modified (PubMed:29211348).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | P57059 | YWHAE P62258 | 4 | EBI-1181640, EBI-356498 | |
BINARY | P57059 | YWHAZ P63104 | 5 | EBI-1181640, EBI-347088 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 27-278 | Protein kinase | ||||
Sequence: YDIERTLGKGNFAVVKLARHRVTKTQVAIKIIDKTRLDSSNLEKIYREVQLMKLLNHPHIIKLYQVMETKDMLYIVTEFAKNGEMFDYLTSNGHLSENEARKKFWQILSAVEYCHDHHIVHRDLKTENLLLDGNMDIKLADFGFGNFYKSGEPLSTWCGSPPYAAPEVFEGKEYEGPQLDIWSLGVVLYVLVCGSLPFDGPNLPTLRQRVLEGRFRIPFFMSQDCESLIRRMLVVDPARRITIAQIRQHRWM | ||||||
Domain | 303-343 | UBA | ||||
Sequence: DYDEQALGIMQTLGVDRQRTVESLQNSSYNHFAAIYYLLLE | ||||||
Region | 353-377 | Disordered | ||||
Sequence: CARPGPARQPRPRSSDLSGLEVPQE | ||||||
Region | 449-477 | Disordered | ||||
Sequence: RQGPGLEEEQDTQESLPSSTGRRHTLAEV | ||||||
Compositional bias | 457-477 | Polar residues | ||||
Sequence: EQDTQESLPSSTGRRHTLAEV | ||||||
Region | 583-612 | RK-rich region; required for cAMP responsiveness and nuclear localization | ||||
Sequence: LKAFRQQLRKTTRTKGFLGLNKIKGLARQV | ||||||
Region | 619-643 | Disordered | ||||
Sequence: RASRGGLSPFHAPAQSPGLHGGAAG |
Domain
The RK-rich region determines the subcellular location and is required for cAMP responsiveness.
Sequence similarities
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length783
- Mass (Da)84,902
- Last updated2005-02-15 v2
- ChecksumD646123C0715DAAC
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A2R8Y6E4 | A0A2R8Y6E4_HUMAN | SIK1 | 153 |
Features
Showing features for sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 166 | in Ref. 3; BAA95536 | ||||
Sequence: A → AGTE | ||||||
Compositional bias | 457-477 | Polar residues | ||||
Sequence: EQDTQESLPSSTGRRHTLAEV | ||||||
Sequence conflict | 489-490 | in Ref. 3; BAA95536 | ||||
Sequence: IV → KF |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AB047786 EMBL· GenBank· DDBJ | BAD74070.1 EMBL· GenBank· DDBJ | mRNA | ||
AP001751 EMBL· GenBank· DDBJ | BAA95536.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC038504 EMBL· GenBank· DDBJ | AAH38504.1 EMBL· GenBank· DDBJ | mRNA | ||
AK131076 EMBL· GenBank· DDBJ | BAC85126.1 EMBL· GenBank· DDBJ | mRNA |