Contents

Search

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: a) cell cycle regulation b) gluconeogenesis & lipogenesis regulation c) muscle growth & differentiation d) 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 [2]

General

serine/threonine kinase

Properties

SIZE: entity length = 783 aa MW = 85 kD COMPARTMENT: cytoplasm cell nucleus STATE: active state MOTIF: kinase domain SITE: 27-278 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 33-41 ATP-binding site NAME: ATP-binding site SITE: 56-56 aspartate residue {D149} Thr phosphorylation site {T182} Ser phosphorylation site {S186} UBA domain {303-343} MOTIF: Thr phosphorylation site {T322} Ser phosphorylation site {S435} Thr phosphorylation site {T460} Thr phosphorylation site {T479} Ser phosphorylation site {S575} RK-rich region {584-610}

Database Correlations

OMIM 605705 UniProt P57059 Pfam PF00069 Entrez Gene 150094 Kegg hsa:150094 ENZYME 2.7.11.1

References

  1. UniProt :accession P57059
  2. Cheng H et al SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis. Sci Signal. 2009 Jul 21;2(80):ra35. PMID: 19622832