SIK2_MOUSE
ID SIK2_MOUSE Reviewed; 931 AA.
AC Q8CFH6;
DT 15-FEB-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=Serine/threonine-protein kinase SIK2;
DE EC=2.7.11.1 {ECO:0000269|PubMed:12624099, ECO:0000269|PubMed:29211348};
DE AltName: Full=Salt-inducible kinase 2;
DE Short=SIK-2;
DE AltName: Full=Serine/threonine-protein kinase SNF1-like kinase 2;
GN Name=Sik2; Synonyms=Snf1lk2;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1] {ECO:0000305, ECO:0000312|EMBL:BAC53845.1}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, COFACTOR,
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND MUTAGENESIS OF LYS-49.
RC TISSUE=Adipose tissue {ECO:0000312|EMBL:BAC53845.1};
RX PubMed=12624099; DOI=10.1074/jbc.m211770200;
RA Horike N., Takemori H., Katoh Y., Doi J., Min L., Asano T., Sun X.J.,
RA Yamamoto H., Kasayama S., Muraoka M., Nonaka Y., Okamoto M.;
RT "Adipose-specific expression, phosphorylation of Ser794 in insulin receptor
RT substrate-1, and activation in diabetic animals of salt-inducible kinase-
RT 2.";
RL J. Biol. Chem. 278:18440-18447(2003).
RN [2]
RP FUNCTION, ACTIVITY REGULATION, PHOSPHORYLATION AT THR-175 AND SER-587, AND
RP MUTAGENESIS OF LYS-49 AND THR-175.
RX PubMed=16817901; DOI=10.1111/j.1742-4658.2006.05291.x;
RA Katoh Y., Takemori H., Lin X.-Z., Tamura M., Muraoka M., Satoh T.,
RA Tsuchiya Y., Min L., Doi J., Miyauchi A., Witters L.A., Nakamura H.,
RA Okamoto M.;
RT "Silencing the constitutive active transcription factor CREB by the LKB1-
RT SIK signaling cascade.";
RL FEBS J. 273:2730-2748(2006).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-532; SER-534 AND SER-587, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Lung, Pancreas, and
RC Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH 14-3-3
RP PROTEINS, MUTAGENESIS OF THR-175; SER-343; SER-358; THR-484; SER-587 AND
RP 595-THR--MET-624, AND PHOSPHORYLATION AT SER-358 AND THR-484.
RX PubMed=29211348; DOI=10.1111/febs.14351;
RA Sonntag T., Vaughan J.M., Montminy M.;
RT "14-3-3 proteins mediate inhibitory effects of cAMP on salt-inducible
RT kinases (SIKs).";
RL FEBS J. 285:467-480(2018).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=34732767; DOI=10.1038/s41598-021-00986-0;
RA Nefla M., Darling N.J., van Gijsel Bonnello M., Cohen P., Arthur J.S.C.;
RT "Salt inducible kinases 2 and 3 are required for thymic T cell
RT development.";
RL Sci. Rep. 11:21550-21550(2021).
CC -!- FUNCTION: Serine/threonine-protein kinase that plays a role in many
CC biological processes such as fatty acid oxidation, autophagy, immune
CC response or glucose metabolism (PubMed:12624099, PubMed:16817901,
CC PubMed:29211348). Phosphorylates 'Ser-794' of IRS1 in insulin-
CC stimulated adipocytes, potentially modulating the efficiency of insulin
CC signal transduction (PubMed:12624099). Inhibits CREB activity by
CC phosphorylating and repressing TORCs, the CREB-specific coactivators
CC (PubMed:16817901). Phosphorylates EP300 and thus inhibits its histone
CC acetyltransferase activity. In turn, regulates the DNA-binding ability
CC of several transcription factors such as PPARA or MLXIPL (By
CC similarity). Also plays a role in thymic T-cell development
CC (PubMed:34732767). {ECO:0000250|UniProtKB:Q9H0K1,
CC ECO:0000269|PubMed:12624099, ECO:0000269|PubMed:16817901,
CC ECO:0000269|PubMed:29211348, ECO:0000269|PubMed:34732767}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:12624099, ECO:0000269|PubMed:29211348};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:12624099,
CC ECO:0000269|PubMed:29211348};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:12624099};
CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-175 (By
CC similarity). Inhibited by phosphorylation at Ser-343, Ser-358, Thr-484
CC and/or Ser-587, probably by PKA, which triggers interaction with 14-3-3
CC proteins (PubMed:29211348). {ECO:0000250|UniProtKB:Q9H0K1,
CC ECO:0000269|PubMed:29211348}.
CC -!- SUBUNIT: Interacts with and phosphorylates TORC2/CRTC2
CC (PubMed:29211348). Interacts (when phosphorylated at Ser-343, Ser-358,
CC Thr-484 and/or Ser-587) with 14-3-3 proteins; the interaction inhibits
CC its kinase activity towards TORCs (PubMed:29211348). There is a
CC cooperative effect of the phosphorylation sites in 14-3-3 binding as
CC the interaction is stronger when more sites are modified.
CC {ECO:0000269|PubMed:29211348}.
CC -!- INTERACTION:
CC Q8CFH6; P61809: Cdk5r1; NbExp=3; IntAct=EBI-16094102, EBI-7840438;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12624099}.
CC -!- TISSUE SPECIFICITY: Present in both white and brown adipose tissues
CC with levels increasing during adipocyte differentiation. Lower levels
CC observed in the testis. {ECO:0000269|PubMed:12624099}.
CC -!- DOMAIN: The RK-rich region is required for cAMP responsiveness.
CC {ECO:0000269|PubMed:29211348}.
CC -!- PTM: Phosphorylated at Thr-175 by STK11/LKB1 in complex with STE20-
CC related adapter-alpha (STRADA) pseudo kinase and CAB39 (By similarity).
CC Phosphorylated at Thr-484 in response to insulin in adipocytes (By
CC similarity). Phosphorylation at Ser-358, Thr-484 and/or Ser-587
CC following cAMP signaling is required for 14-3-3 interaction and thus
CC inactivation (PubMed:29211348). {ECO:0000250|UniProtKB:Q9H0K1,
CC ECO:0000269|PubMed:29211348}.
CC -!- PTM: Acetylation at Lys-53 inhibits kinase activity. Deacetylated by
CC HDAC6 (By similarity). {ECO:0000250|UniProtKB:Q9H0K1}.
CC -!- DISRUPTION PHENOTYPE: Constitutive knockout combined with conditional
CC knockout of SIK3 in the haemopoietic cells results in a severe
CC reduction in peripheral T-cells without reducing B-cell number.
CC {ECO:0000269|PubMed:34732767}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC protein kinase family. SNF1 subfamily. {ECO:0000305}.
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DR EMBL; AB067780; BAC53845.1; -; mRNA.
DR CCDS; CCDS40627.1; -.
DR RefSeq; NP_848825.2; NM_178710.3.
DR AlphaFoldDB; Q8CFH6; -.
DR SMR; Q8CFH6; -.
DR BioGRID; 231647; 3.
DR DIP; DIP-60734N; -.
DR IntAct; Q8CFH6; 1.
DR STRING; 10090.ENSMUSP00000038761; -.
DR iPTMnet; Q8CFH6; -.
DR PhosphoSitePlus; Q8CFH6; -.
DR jPOST; Q8CFH6; -.
DR MaxQB; Q8CFH6; -.
DR PaxDb; Q8CFH6; -.
DR PRIDE; Q8CFH6; -.
DR ProteomicsDB; 261363; -.
DR DNASU; 235344; -.
DR GeneID; 235344; -.
DR KEGG; mmu:235344; -.
DR CTD; 23235; -.
DR MGI; MGI:2445031; Sik2.
DR eggNOG; KOG0586; Eukaryota.
DR InParanoid; Q8CFH6; -.
DR OrthoDB; 1127668at2759; -.
DR PhylomeDB; Q8CFH6; -.
DR BioGRID-ORCS; 235344; 4 hits in 77 CRISPR screens.
DR ChiTaRS; Sik2; mouse.
DR PRO; PR:Q8CFH6; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q8CFH6; protein.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0042149; P:cellular response to glucose starvation; IBA:GO_Central.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:MGI.
DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0046626; P:regulation of insulin receptor signaling pathway; IDA:UniProtKB.
DR CDD; cd14071; STKc_SIK; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR017090; Ser/Thr_kinase_SIK1/2.
DR InterPro; IPR034672; SIK.
DR InterPro; IPR015940; UBA.
DR Pfam; PF00069; Pkinase; 1.
DR PIRSF; PIRSF037014; Ser/Thr_PK_SNF1-like; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS50030; UBA; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Cytoplasm; Kinase; Magnesium; Metal-binding;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..931
FT /note="Serine/threonine-protein kinase SIK2"
FT /id="PRO_0000086663"
FT DOMAIN 20..271
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 295..335
FT /note="UBA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212"
FT REGION 565..586
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 595..624
FT /note="RK-rich region; required for cAMP responsiveness"
FT /evidence="ECO:0000269|PubMed:29211348"
FT REGION 631..662
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 744..768
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 798..842
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 801..838
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 142
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:Q13131,
FT ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-
FT ProRule:PRU10027"
FT BINDING 26..34
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q13131,
FT ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 49
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:12624099"
FT MOD_RES 25
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9H0K1"
FT MOD_RES 53
FT /note="N6-acetyllysine; by EP300"
FT /evidence="ECO:0000250|UniProtKB:Q9H0K1"
FT MOD_RES 175
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:16817901"
FT MOD_RES 358
FT /note="Phosphoserine"
FT /evidence="ECO:0000305|PubMed:29211348"
FT MOD_RES 484
FT /note="Phosphothreonine"
FT /evidence="ECO:0000305|PubMed:29211348"
FT MOD_RES 532
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 534
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 587
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MUTAGEN 49
FT /note="K->M: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:12624099,
FT ECO:0000269|PubMed:16817901"
FT MUTAGEN 175
FT /note="T->A: Reduced inhibitory activity towards TORCs in
FT presence and absence of cAMP signaling."
FT /evidence="ECO:0000269|PubMed:16817901"
FT MUTAGEN 175
FT /note="T->E: Low levels of constitutive activity."
FT /evidence="ECO:0000269|PubMed:16817901"
FT MUTAGEN 343
FT /note="S->A: Reduced interaction with 14-3-3 proteins in
FT response to cAMP signaling and, thus, still able to inhibit
FT TORC activity."
FT /evidence="ECO:0000269|PubMed:29211348"
FT MUTAGEN 358
FT /note="S->A: Reduced interaction with 14-3-3 proteins in
FT response to cAMP signaling and, thus, still able to inhibit
FT TORC activity. Resistant to inhibition by cAMP signaling
FT and, thus, still able to inhibit TORC activity; when
FT associated with A-484 and A-587."
FT /evidence="ECO:0000269|PubMed:29211348"
FT MUTAGEN 484
FT /note="T->A: Reduced interaction with 14-3-3 proteins in
FT response to cAMP signaling and, thus, still able to inhibit
FT TORC activity. Resistant to inhibition by cAMP signaling
FT and, thus, still able to inhibit TORC activity; when
FT associated with A-358 and A-587."
FT /evidence="ECO:0000269|PubMed:29211348"
FT MUTAGEN 587
FT /note="S->A: Reduced interaction with 14-3-3 proteins in
FT response to cAMP signaling and, thus, still able to inhibit
FT TORC activity. Resistant to inhibition by cAMP signaling
FT and, thus, still able to inhibit TORC activity; when
FT associated with A-358 and A-484."
FT /evidence="ECO:0000269|PubMed:29211348"
FT MUTAGEN 595..624
FT /note="Missing: Reduced 14-3-3 interaction. Reduced
FT inactivation following cAMP signaling."
FT /evidence="ECO:0000269|PubMed:29211348"
SQ SEQUENCE 931 AA; 104198 MW; 5CF2FB8DCDC689F4 CRC64;
MVMADGPRHL QRGPVRVGFY DIEGTLGKGN FAVVKLGRHR TTKTEVAIKI IDKSQLDAVN
LEKIYREVQI MKMLDHPHII KLYQVMETKS MLYLVTEYAK NGEIFDYLAN HGRLNESEAR
RKFWQILSAV DYCHGRKVVH RDLKAENLLL DNNMNIKIAD FGFGNFFKTG ELLATWCGSP
PYAAPEVFEG QQYEGPQLDI WSMGVVLYVL VCGALPFDGP TLPILRQRVL EGRFRIPYFM
SEDCEHLIRR MLVLDPSKRL SIAQIKEHKW MLIEVPVQRP ILYPQEQENE PSIGEFNEQV
LRLMHSLGID QQKTVESLQN KSYNHFAAIY FLLVERLKSH RSSFPVEQRL DGRQRRPSTI
AEQTVAKAQT VGLPVTLHPP NVRLMRSTLL PQASNVEAFS FPTSSCQAEA AFMEEECVDT
PKVNGCLLDP VPPVLVRKGC QSLPSSMMET SIDEGLETEG EAEEDPSQAF EAFQATRSGQ
RRHTLSEVTN QLVVMPGAGK MFSMSDNPSL ESVDSEYDMG SAQRDLNFLE DSPSLKDIML
ANQPSPRMTS PFISLRPANP AMQALSSQKR EAHNRSPVSF REGRRASDTS LTQGIVAFRQ
HLQNLARTKG ILELNKVQLL YEQMGSNADP TLTSTAPQLQ DLSSSCPQEE ISQQQESVSS
LSASMHPQLS PQQSLETQYL QHRLQKPNLL PKAQSPCPVY CKEPPRSLEQ QLQEHRLQQK
RLFLQKQSQL QAYFNQMQIA ESSYPGPSQQ LALPHQETPL TSQQPPSFSL TQALSPVLEP
SSEQMQFSSF LSQYPEMQLQ PLPSTPGPRA PPPLPSQLQQ HQQPPPPPPP PPPQQPGAAP
TSLQFSYQTC ELPSTTSSVP NYPASCHYPV DGAQQSNLTG ADCPRSSGLQ DTASSYDPLA
LSELPGLFDC EMVEAVDPQH NGVVSCLARE T
