P57059
uniprot
P57059
canonical
activity_regulation
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). {ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:29211348}.
uniprot
proteins
amino_acid_sequence
MVIMSEFSADPAGQGQGQQKPLRVGFYDIERTLGKGNFAVVKLARHRVTKTQVAIKIIDKTRLDSSNLEKIYREVQLMKLLNHPHIIKLYQVMETKDMLYIVTEFAKNGEMFDYLTSNGHLSENEARKKFWQILSAVEYCHDHHIVHRDLKTENLLLDGNMDIKLADFGFGNFYKSGEPLSTWCGSPPYAAPEVFEGKEYEGPQLDIWSLGVVLYVLVCGSLPFDGPNLPTLRQRVLEGRFRIPFFMSQDCESLIRRMLVVDPARRITIAQIRQHRWMRAEPCLPGPACPAFSAHSYTSNLGDYDEQALGIMQTLGVDRQRTVESLQNSSYNHFAAIYYLLLERLKEYRNAQCARPGPARQPRPRSSDLSGLEVPQEGLSTDPFRPALLCPQPQTLVQSVLQAEMDCELQSSLQWPLFFPVDASCSGVFRPRPVSPSSLLDTAISEEARQGPGLEEEQDTQESLPSSTGRRHTLAEVSTRLSPLTAPCIVVSPSTTASPAEGTSSDSCLTFSASKSPAGLSGTPATQGLLGACSPVRLASPFLGSQSATPVLQAQGGLGGAVLLPVSFQEGRRASDTSLTQGLKAFRQQLRKTTRTKGFLGLNKIKGLARQVCQAPASRASRGGLSPFHAPAQSPGLHGGAAGSREGWSLLEEVLEQQRLLQLQHHPAAAPGCSQAPQPAPAPFVIAPCDGPGAAPLPSTLLTSGLPLLPPPLLQTGASPVASAAQLLDTHLHIGTGPTALPAVPPPRLARLAPGCEPLGLLQGDCEMEDLMPCSLGTFVLVQ
uniprot
proteins
disease_involvement
DISEASE: Developmental and epileptic encephalopathy 30 (DEE30) [MIM:616341]: A 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. {ECO:0000269|PubMed:25839329}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Note=Defects in SIK1 may be associated with some cancers, such as breast cancers. Loss of SIK1 correlates with poor patient outcome in breast cancers (PubMed:19622832). {ECO:0000269|PubMed:19622832}.
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
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). {ECO:0000250|UniProtKB:Q60670, ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:16306228, ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:19622832, ECO:0000269|PubMed:29211348}.
uniprot
proteins
mass_dalton
84902
uniprot
proteins
mutagenesis
MUTAGEN 56; /note="K->M: Loss of kinase activity."; /evidence="ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:19622832"; MUTAGEN 135; /note="S->A: Decreased kinase activity without affecting much autophosphorylation status."; /evidence="ECO:0000269|PubMed:18348280"; MUTAGEN 182; /note="T->A: Prevents phosphorylation and activation by STK11/LKB1 complex. Reduced inhibition of CRTC3-mediated transcriptional activity."; /evidence="ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:29211348"; MUTAGEN 186; /note="S->A,D,C,G: Impaired autophosphorylation and kinase activity."; /evidence="ECO:0000269|PubMed:18348280"; MUTAGEN 186; /note="S->T: Does not autophosphorylation and kinase activity."; /evidence="ECO:0000269|PubMed:18348280"; MUTAGEN 209; /note="S->A: Decreased kinase activity without affecting much autophosphorylation status."; /evidence="ECO:0000269|PubMed:18348280"; MUTAGEN 248; /note="S->A: Decreased kinase activity without affecting much autophosphorylation status."; /evidence="ECO:0000269|PubMed:18348280"; MUTAGEN 473; /note="T->A: 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."; /evidence="ECO:0000269|PubMed:29211348"; MUTAGEN 473; /note="T->E: Reduced but still present interaction with 14-3-3 proteins in response to cAMP signaling and, thus, still able to inhibit TORC activity."; /evidence="ECO:0000269|PubMed:29211348"; MUTAGEN 575; /note="S->A: 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."; /evidence="ECO:0000269|PubMed:29211348"; MUTAGEN 575; /note="S->E: Strongly reduced but still present interaction with 14-3-3 proteins in response to cAMP signaling and, thus, still able to inhibit TORC activity."; /evidence="ECO:0000269|PubMed:29211348
uniprot
proteins
post_translational_modification
PTM: 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. {ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:29211348}.
uniprot
proteins
protein_family
AMPK subfamily
uniprot
proteins
protein_family
CAMK Ser/Thr protein kinase family
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
pubmed
10830953
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
14976552
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16306228
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
18348280
uniprot
proteins
pubmed
19622832
uniprot
proteins
pubmed
25839329
uniprot
proteins
pubmed
29211348
uniprot
proteins
sequence_length
783
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16306228, ECO:0000269|PubMed:29211348}. Nucleus {ECO:0000269|PubMed:16306228, ECO:0000269|PubMed:29211348}. Note=Locates to cytoplasm when inactive following cAMP-induced phosphorylation, probably by PKA (PubMed:29211348).
uniprot
proteins