Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

SIK1 (P57059) - Overview - Molecular Target Synopsis

Protein


SIK1, Serine/threonine-protein kinase SIK1
Enzyme Classification 2.7.11.1
UniProt P57059

Also Known as SIK1_HUMAN, SIK1, SIK, SNF1LK

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. Interacts with ATP1A1 (By similarity). Interacts (when phosphorylated on Thr-182 and Ser-186) with YWHAZ (PubMed:16306228). Interacts (when phosphorylated at Thr-473 and/or Ser-575) with 14-3-3 proteins; the interaction inhibits kinase activity towards TORCs (PubMed:29211348). There is a cooperative effect of the phosphorylation sites in 14-3-3 binding as the interaction is stronger when both Thr-473 and Ser-575 are modified (PubMed:29211348).

Isoforms / Transcripts (Protein Coding)


Protein Length Ensembl Gene Ensembl Transcript Ensembl Protein Uniprot Isoform
783ENSG00000142178ENST00000270162ENSP00000270162P57059-1

Sub-cellular localization


UniProt: SIK1 is active in the following subcellular-locations: cytoplasm, nucleus.
GO terms: SIK1 is active in the following subcellular-locations: cytoplasm, nucleotide-activated protein kinase complex, nucleus.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project SIK1 has gain in 0 cell-lines, loss in 2 cell-lines and no signal in 1003 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: A549, NCI_H460, A498

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: HCC-15, NCI-H292, HEp-2

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, NHLF, HMEC

(see details)

RNA Interference


SIK1 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: 93VU, RMGI. (see details)

3D Structures


At greater than 50% identity similarity to SIK1 there are:
19 structures (47 chains) solved
4 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


SIK1 has been screened with 642 compounds (1225 bioactivities), 17 compounds have bioactivities that show binding affinity of <= 500nM (22 bioactivities). (see details)