Salt-inducible kinase (SIK) (SIK)

Salt-inducible kinases (SIKs) are a family of serine/threonine kinases (SIK1, SIK2, and SIK3) that have recently emerged as critical regulators of the YAP/TAZ mechanotransduction pathway. While the core Hippo pathway (MST/LATS) was traditionally thought to be the primary regulator of YAP/TAZ, SIKs have been identified as a "novel" or parallel mechanism that transduces mechanical cues, such as extracellular matrix stiffness and cell shape, to control YAP/TAZ activity. SIKs phosphorylate YAP and TAZ, promoting their cytoplasmic sequestration and degradation, thereby inhibiting their oncogenic transcriptional activity. In many cancers and fibrotic diseases, SIK activity is dysregulated, leading to the aberrant activation of YAP/TAZ and subsequent disease progression. Consequently, SIK inhibitors are being developed as therapeutic agents to suppress YAP/TAZ-driven tumorigenesis and fibrosis. These inhibitors work by blocking SIK-mediated phosphorylation, allowing for the modulation of the Hippo-independent mechanotransduction axis.

Other names

SIK1SIK2SIK3Salt-inducible kinase 1Salt-inducible kinase 2Salt-inducible kinase 3SNF1-like kinase

Inhibition of SIK kinase activity leads to the dephosphorylation and nuclear translocation of YAP and TAZ, thereby modulating the Hippo signaling pathway and its downstream transcriptional programs.