serine/threonine protein kinase SIK1; salt-inducible protein kinase 1; SIK-1; serine/threonine protein kinase SNF1-like kinase 1; serine/threonine protein kinase SNF1LK (SIK1, SIK, SNF1LK)

Function

• serine/threonine protein kinase
• role in:
  • cell cycle regulation
  • gluconeogenesis & lipogenesis regulation
  • muscle growth & differentiation
  • tumor suppression
• phosphorylates HDAC4, HDAC5, PPME1, SREBF1, TORC1/CRTC1 & TORC2/CRTC2
• acts as a tumor suppressor & 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
  • able to suppress metastasis
• part of a Na+-sensing signaling network, probably by mediating phosphorylation of PPME1
  • following increases in intracellular Na+, SIK1 is activated by CaMK1 & phosphorylates PPME1 subunit of protein phosphatase 2A (PP2A), leading to dephosphorylation of Na+/K+-transporting ATPase ATP1A1 & subsequent increase activity of ATP1A1
• acts as a regulator of muscle cells by phosphorylating & inhibiting class II histone deacetylases HDAC4 & HDAC5, leading to expression of MEF2 target genes in myocytes
• 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 & repressing the CREB-specific coactivators TORC1/CRTC1 & TORC2/CRTC2, inhibiting CREB activity
• regulates hepatic lipogenesis by phosphorylating & inhibiting SREBF1
• activated by phosphorylation on Thr-182
• also activated by phosphorylation on Thr-322 in response to increases in intracellular Na+ in parallel with elevations in intracellular Ca+2 through the reversible Na+/Ca+2 exchanger; activated by phosphorylation at Thr-322 by CaMK1
• phosphorylated at Thr-182 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase & 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 by PKA promotes translocation to the cytoplasm
• phosphorylated upon DNA damage, probably by ATM or ATR
• interacts with ATP1A1 (putative)
• interacts (when phosphorylated on Thr-182 & Ser-186) with YWHAZ

Cofactor: Mg+2 (putative)

Structure

• the RK-rich region determines the subcellular location
• belongs to the protein kinase superfamily, CAMK Ser/Thr protein kinase family, AMPK subfamily
• contains 1 protein kinase domain
• contains 1 UBA domain

Compartment

• cytoplasm, nucleus
• following ACTH treatment & subsequent phosphorylation by PKA, translocates to the cytoplasm, where it binds to YWHAZ

Pathology

• defects in SIK1 may be associated with some cancers, such as breast cancers
• loss of SIK1 correlates with poor patient outcome in breast cancers

More general terms

• serine/threonine kinase

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=150094
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:150094
• OMIM: https://mirror.omim.org/entry/605705
• UniProt: http://www.uniprot.org/uniprot/P57059.html