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Q69Z98 (BRSK2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 88. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
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Names and origin

Protein namesRecommended name:
Serine/threonine-protein kinase BRSK2
EC=2.7.11.1
EC=2.7.11.26
Alternative name(s):
Brain-specific serine/threonine-protein kinase 2
Short name=BR serine/threonine-protein kinase 2
Serine/threonine-protein kinase SAD-A
Gene names
Name:Brsk2
Synonyms:Kiaa4256, Sada
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length735 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine-protein kinase that plays a key role in polarization of neurons and axonogenesis, cell cycle progress and insulin secretion. Phosphorylates CDK16, CDC25C, MAPT/TAU, PAK1 and WEE1. Following phosphorylation and activation by STK11/LKB1, acts as a key regulator of polarization of cortical neurons, probably by mediating phosphorylation of microtubule-associated proteins such as MAPT/TAU at 'Thr-504' and 'Ser-554'. Also regulates neuron polarization by mediating phosphorylation of WEE1 at 'Ser-642' in post-mitotic neurons, leading to down-regulate WEE1 activity in polarized neurons. Plays a role in the regulation of the mitotic cell cycle progress and the onset of mitosis. Plays a role in the regulation of insulin secretion in response to elevated glucose levels, probably via phosphorylation of CDK16 and PAK1. While BRSK2 phosphorylated at Thr-175 can inhibit insulin secretion (Ref.9), BRSK2 phosphorylated at Thr-261 can promote insulin secretion (Ref.8). Regulates reorganization of the actin cytoskeleton. May play a role in the apoptotic response triggered by endoplasmatic reticulum (ER) stress. Ref.1 Ref.6 Ref.7 Ref.8 Ref.9

Catalytic activity

ATP + a protein = ADP + a phosphoprotein. Ref.8

ATP + [tau protein] = ADP + [tau protein] phosphate. Ref.8

Cofactor

Magnesium By similarity.

Enzyme regulation

Activated by phosphorylation on Thr-175 by STK11/LKB1.

Subunit structure

Interacts with FZR1, a regulatory subunit of the APC ubiquitin ligase complex. Interacts with COPS5. Interacts with PAK1 By similarity. Ref.8

Subcellular location

Cytoplasm › cytoskeleton › microtubule organizing center › centrosome By similarity. Cytoplasm › perinuclear region By similarity. Endoplasmic reticulum By similarity. Note: Detected at centrosomes during mitosis. Localizes to the endoplasmic reticulum in response to stress caused by tunicamycin By similarity.

Tissue specificity

Detected in pancreas islets and in brain (at protein level). Detected in brain and pancreas. Ref.9

Domain

The KEN box motif is required for interaction with FZR1/CDH1 and essential for APC(CDH1)-mediated ubiquitination By similarity.

Post-translational modification

May be phosphorylated at Thr-261 by PKA By similarity. Phosphorylated at Thr-175 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Not phosphorylated at Thr-175 by CaMKK2. In contrast, it is phosphorylated and activated by CaMKK1. May be inactivated via dephosphorylation of Thr-175 by PP2C. Ref.6

Polyubiquitinated by the APC complex in conjunction with FZR1, leading to its proteasomal degradation. Targeted for proteasomal degradation by interaction with COPS5. BRSK2 levels change during the cell cycle. BRSK2 levels are low at the G1/S boundary and gradually increase as cells progress into G2 phase. BRSK2 levels decrease rapidly at the end of mitosis By similarity.

Disruption phenotype

No visible phenotype. Mice are fertile and healthy. In contrast, mice lacking both Brsk1 and Brsk2 show little spontaneous movement and are only weakly responsive to tactile stimulation: they die within 2 hours of birth. Defects are due to impaired neuronal differentiation and polarity. Ref.1

Sequence similarities

Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily.

Contains 1 protein kinase domain.

Contains 1 UBA domain.

Ontologies

Keywords
   Biological processApoptosis
Cell cycle
Cell division
Exocytosis
Mitosis
Neurogenesis
   Cellular componentCytoplasm
Cytoskeleton
Endoplasmic reticulum
   Coding sequence diversityAlternative splicing
   LigandATP-binding
Magnesium
Metal-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processG2/M transition of mitotic cell cycle

Inferred from electronic annotation. Source: Ensembl

actin cytoskeleton reorganization

Inferred from electronic annotation. Source: Ensembl

axonogenesis

Inferred from mutant phenotype Ref.6. Source: UniProtKB

establishment of cell polarity

Inferred from mutant phenotype Ref.6. Source: UniProtKB

exocytosis

Inferred from electronic annotation. Source: UniProtKB-KW

intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress

Inferred from electronic annotation. Source: Ensembl

mitosis

Inferred from electronic annotation. Source: UniProtKB-KW

neuron differentiation

Inferred from genetic interaction Ref.1. Source: UniProtKB

neuron projection morphogenesis

Inferred from genetic interaction Ref.7. Source: MGI

peptidyl-serine phosphorylation

Inferred from direct assay Ref.7. Source: MGI

protein phosphorylation

Inferred from direct assay Ref.1. Source: UniProtKB

regulation of insulin secretion involved in cellular response to glucose stimulus

Inferred from mutant phenotype Ref.9. Source: UniProtKB

   Cellular_componentcentrosome

Inferred from electronic annotation. Source: Ensembl

endoplasmic reticulum

Inferred from electronic annotation. Source: UniProtKB-SubCell

perinuclear region of cytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

magnesium ion binding

Inferred by curator Ref.1. Source: UniProtKB

protein kinase binding

Inferred from physical interaction Ref.6. Source: UniProtKB

protein serine/threonine kinase activity

Inferred from direct assay Ref.1. Source: UniProtKB

tau-protein kinase activity

Inferred from direct assay Ref.1. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q69Z98-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q69Z98-2)

Also known as: SADA-beta;

The sequence of this isoform differs from the canonical sequence as follows:
     648-735: DTTNCMEVMT...GPPAARREQP → EPPPPAPGLSWGAGLKGQKVATSYESSL
Note: No experimental confirmation available.
Isoform 3 (identifier: Q69Z98-3)

Also known as: SADA-gamma;

The sequence of this isoform differs from the canonical sequence as follows:
     664-679: Missing.
Note: No experimental confirmation available.
Isoform 4 (identifier: Q69Z98-4)

Also known as: SADA-alpha;

The sequence of this isoform differs from the canonical sequence as follows:
     648-653: DTTNCM → GIIPKS
     654-735: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 735735Serine/threonine-protein kinase BRSK2
PRO_0000274036

Regions

Domain20 – 271252Protein kinase
Domain298 – 34043UBA
Nucleotide binding26 – 349ATP By similarity
Motif604 – 6063KEN box By similarity
Compositional bias425 – 46945Pro-rich

Sites

Active site1421Proton acceptor By similarity
Binding site491ATP By similarity

Amino acid modifications

Modified residue1751Phosphothreonine; by LKB1 Ref.6
Modified residue2611Phosphothreonine; by PKA By similarity
Modified residue3681Phosphoserine By similarity
Modified residue3831Phosphoserine By similarity
Modified residue3941Phosphoserine By similarity
Modified residue4131Phosphoserine By similarity
Modified residue4231Phosphothreonine By similarity
Modified residue5101Phosphothreonine By similarity

Natural variations

Alternative sequence648 – 73588DTTNC…RREQP → EPPPPAPGLSWGAGLKGQKV ATSYESSL in isoform 2.
VSP_022605
Alternative sequence648 – 6536DTTNCM → GIIPKS in isoform 4.
VSP_022607
Alternative sequence654 – 73582Missing in isoform 4.
VSP_022608
Alternative sequence664 – 67916Missing in isoform 3.
VSP_022606

Experimental info

Mutagenesis491K → A: Loss of kinase activity. Ref.1
Mutagenesis1751T → A: Prevents phosphorylation and activation by STK11/LKB1 complex. Ref.6
Sequence conflict31 – 4313TGLVK…HCVTC → VDGDLLASDTVDS in BAD32546. Ref.4

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified January 23, 2007. Version 2.
Checksum: A37FCC6CC7253F11

FASTA73581,733
        10         20         30         40         50         60 
MTSTGKDGGG AQHAQYVGPY RLEKTLGKGQ TGLVKLGIHC VTCQKVAIKI VNREKLSESV 

        70         80         90        100        110        120 
LMKVEREIAI LKLIEHPHVL KLHDVYENKK YLYLVLEHVS GGELFDYLVK KGRLTPKEAR 

       130        140        150        160        170        180 
KFFRQIISAL DFCHSHSICH RDLKPENLLL DERNNIRIAD FGMASLQVGD SLLETSCGSP 

       190        200        210        220        230        240 
HYACPEVIRG EKYDGRKADV WSCGVILFAL LVGALPFDDD NLRQLLEKVK RGVFHMPHFI 

       250        260        270        280        290        300 
PPDCQSLLRG MIEVDAARRL TLEHIQKHIW YIGGKNEPEP EQPIPRKVQI RSLPSLEDID 

       310        320        330        340        350        360 
PDVLDSMHSL GCFRDRNKLL QDLLSEEENQ EKMIYFLLLD RKERYPSHED EDLPPRNEID 

       370        380        390        400        410        420 
PPRKRVDSPM LNRHGKRRPE RKSMEVLSVT DGGSPVPARR AIEMAQHGQR SRSISGASSG 

       430        440        450        460        470        480 
LSTSPLSSPR VTPHPSPRGS PLPTPKGTPV HTPKESPAGT PNPTPPSSPS VGGVPWRTRL 

       490        500        510        520        530        540 
NSIKNSFLGS PRFHRRKLQV PTPEEMSNLT PESSPELAKK SWFGNFINLE KEEQIFVVIK 

       550        560        570        580        590        600 
DKPLSSIKAD IVHAFLSIPS LSHSVISQTS FRAEYKATGG PAVFQKPVKF QVDITYTEGG 

       610        620        630        640        650        660 
EAQKENGIYS VTFTLLSGPS RRFKRVVETI QAQLLSTHDQ PSAQHLSDTT NCMEVMTGRL 

       670        680        690        700        710        720 
SKCGTPLSNF FDVIKQLFSD EKNGQAAQAP STPAKRSAHG PLGDSAAAGP GGDTEYPMGK 

       730 
DMAKMGPPAA RREQP

« Hide

Isoform 2 (SADA-beta) [UniParc].

Checksum: B01D8D8F9C24C71F
Show »

FASTA67575,361
Isoform 3 (SADA-gamma) [UniParc].

Checksum: 4C2ABA57205974AB
Show »

FASTA71979,938
Isoform 4 (SADA-alpha) [UniParc].

Checksum: 8A23B94D71850E9A
Show »

FASTA65373,150

References

« Hide 'large scale' references
[1]"Mammalian SAD kinases are required for neuronal polarization."
Kishi M., Pan Y.A., Crump J.G., Sanes J.R.
Science 307:929-932(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3 AND 4), FUNCTION, MUTAGENESIS OF LYS-49, DISRUPTION PHENOTYPE.
[2]Tang W.W., Shan Y.X.
Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
[3]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: C57BL/6J.
[4]"Prediction of the coding sequences of mouse homologues of KIAA gene: IV. The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries."
Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S., Saga Y., Seino S., Nishimura M., Kaisho T., Hoshino K., Kitamura H., Nagase T., Ohara O., Koga H.
DNA Res. 11:205-218(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 31-735 (ISOFORM 1).
Tissue: Fetal brain.
[5]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 131-653 (ISOFORM 4).
Strain: C57BL/6.
Tissue: Brain.
[6]"LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons."
Barnes A.P., Lilley B.N., Pan Y.A., Plummer L.J., Powell A.W., Raines A.N., Sanes J.R., Polleux F.
Cell 129:549-563(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION AT THR-175, MUTAGENESIS OF THR-175.
[7]"Persistence of the cell-cycle checkpoint kinase Wee1 in SadA- and SadB-deficient neurons disrupts neuronal polarity."
Muller M., Lutter D., Puschel A.W.
J. Cell Sci. 123:286-294(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[8]"Synapses of amphids defective (SAD-A) kinase promotes glucose-stimulated insulin secretion through activation of p21-activated kinase (PAK1) in pancreatic beta-Cells."
Nie J., Sun C., Faruque O., Ye G., Li J., Liang Q., Chang Z., Yang W., Han X., Shi Y.
J. Biol. Chem. 287:26435-26444(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH PAK1.
[9]"Brain-selective kinase 2 (BRSK2) phosphorylation on PCTAIRE1 negatively regulates glucose-stimulated insulin secretion in pancreatic beta-cells."
Chen X.Y., Gu X.T., Saiyin H., Wan B., Zhang Y.J., Li J., Wang Y.L., Gao R., Wang Y.F., Dong W.P., Najjar S.M., Zhang C.Y., Ding H.F., Liu J.O., Yu L.
J. Biol. Chem. 287:30368-30375(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ		AY533672 mRNA. Translation: AAT08447.1.
AY533673 mRNA. Translation: AAT08448.1.
AY533674 mRNA. Translation: AAT08449.1.
AY660739 mRNA. Translation: AAT74618.1.
AL603836 Genomic DNA. No translation available.
AL772165 Genomic DNA. No translation available.
AK173268 mRNA. Translation: BAD32546.1.
BC056498 mRNA. Translation: AAH56498.1.
RefSeqNP_001009929.1. NM_001009929.3.
NP_001009930.1. NM_001009930.3.
NP_083702.1. NM_029426.2.
UniGeneMm.274868.
Mm.482784.

3D structure databases

ProteinModelPortalQ69Z98.
SMRQ69Z98. Positions 14-339.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid217728. 1 interaction.
STRING10090.ENSMUSP00000101610.

PTM databases

PhosphoSiteQ69Z98.

Proteomic databases

PaxDbQ69Z98.
PRIDEQ69Z98.

Protocols and materials databases

DNASU75770.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000018971; ENSMUSP00000018971; ENSMUSG00000053046. [Q69Z98-4]
ENSMUST00000075528; ENSMUSP00000074969; ENSMUSG00000053046. [Q69Z98-3]
ENSMUST00000078200; ENSMUSP00000077330; ENSMUSG00000053046. [Q69Z98-2]
ENSMUST00000105989; ENSMUSP00000101610; ENSMUSG00000053046. [Q69Z98-2]
ENSMUST00000174499; ENSMUSP00000134201; ENSMUSG00000053046. [Q69Z98-1]
GeneID75770.
KEGGmmu:75770.
UCSCuc009kme.1. mouse. [Q69Z98-2]
uc009kmf.1. mouse. [Q69Z98-3]
uc009kmg.1. mouse. [Q69Z98-4]
uc009kmi.1. mouse. [Q69Z98-1]

Organism-specific databases

CTD9024.
MGIMGI:1923020. Brsk2.
RougeSearch...

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00750000117372.
HOGENOMHOG000246447.
HOVERGENHBG007240.
InParanoidQ69Z98.
KOK08796.
OMALELPMSQ.
OrthoDBEOG7XSTDH.
PhylomeDBQ69Z98.
TreeFamTF313967.

Gene expression databases

BgeeQ69Z98.
CleanExMM_BRSK2.
GenevestigatorQ69Z98.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 2 hits.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio343904.
PROQ69Z98.
SOURCESearch...

Entry information

Entry nameBRSK2_MOUSE
AccessionPrimary (citable) accession number: Q69Z98
Secondary accession number(s): Q699J3 expand/collapse secondary AC list , Q699J4, Q6DMN7, Q6PHM0
Entry history
Integrated into UniProtKB/Swiss-Prot: January 23, 2007
Last sequence update: January 23, 2007
Last modified: April 16, 2014
This is version 88 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

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