STK3

Description

The STK3 (serine/threonine kinase 3) is a protein-coding gene located on chromosome 8.

Serine/threonine-protein kinase 3 is an enzyme that in humans is encoded by the STK3 gene. Protein kinase activation is a frequent response of cells to treatment with growth factors, chemicals, heat shock, or apoptosis-inducing agents. This protein kinase activation presumably allows cells to resist unfavorable environmental conditions. The yeast 'sterile 20' (Ste20) kinase acts upstream of the mitogen-activated protein kinase (MAPK) cascade that is activated under a variety of stress conditions. MST2 was first identified as a kinase that resembles budding yeast Ste20 (Creasy and Chernoff, 1996) and later as a kinase that is activated by the proapoptotic agents straurosporine and FAS ligand (MIM 134638) (Taylor et al., 1996; Lee et al., 2001).[supplied by OMIM] Human serine/threonine-protein kinase 3 (STK3, or MST2) is a 56,301 Da monomer with three domains: a SARAH domain, composed of a long α-helix at the C-terminus that when dimerized, forms an antiparallel dimeric coiled-coil, an inhibitory domain, and a catalytic kinase domain at the N-terminus. The SARAH (Salvador/RASSF/Hpo) domain has been found to mediate dimeric interactions between MST2 and RASSF enzymes, a class of tumor suppressors that serve an important role in activating apoptosis, as well as between MST2 and SAV1, a non-catalytic polypeptide responsible for bringing MST2 to an apoptotic pathway. When the MST2 kinase domain is in its active state, a threonine residue residing on an alpha helix at the 180th position (T180) is autophosphorylated. STK3 is activated through autophosphorylation by dimerizing with itself or heterodimerizing with its homolog, MST1 (STK4). Heterodimerization has been shown to exhibit a roughly six-fold weaker binding affinity than homodimerization with MST2, as well as lower kinase activity compared to both MST2/MST2 and MST1/MST1 homodimers. In addition to activation by straurosporine and FAS ligand, STK3 has been found to be activated through dissociation of GLRX and Thioredoxin (Trx1) from STK3 under oxidative stress.

STK3 is a stress-activated kinase that promotes programmed cell death (apoptosis). After being cleaved by caspase enzymes, it enters the nucleus and triggers chromatin condensation and DNA fragmentation. STK3 is a crucial component of the Hippo signaling pathway, which controls organ size and suppresses tumor formation. It does so by restricting cell proliferation and promoting apoptosis. This pathway involves a cascade of kinases where STK3 and its close relative STK4, in association with the regulatory protein SAV1, phosphorylate and activate LATS1/2, which in turn phosphorylates and inactivates the YAP1 oncoprotein and WWTR1/TAZ. This inactivation of YAP1 prevents it from entering the nucleus to regulate genes crucial for cell proliferation, death, and migration. STK3 and STK4 are essential for preventing the overgrowth of mature liver cells, suppressing the activation of liver stem cells, and inhibiting tumor development. STK3 also participates in centrosome separation by regulating the localization of NEK2 to the centrosome and its phosphorylation of CROCC and CEP250. It collaborates with SAV1 to enhance the transcriptional activity of ESR1 by modulating its phosphorylation. STK3 also positively regulates RAF1 activation by preventing inhibitory phosphorylation on Ser-259. STK3 interacts with and phosphorylates several proteins, including MOBKL1A, RASSF2, MOBKL1B, and STK38. It forms complexes with proteins like MOBKL1B and STK38. STK3 also interacts with other proteins including NORE1, SAV1, RAF1, RASSF1, NEK2, ESR1, PKB/AKT1, DLG5, LATS1, MARK3, RASSF5, and SLMAP. These interactions regulate STK3's activity and function.

STK3 is also known as KRS1, MST2.

Associated Diseases

WES Whole Exome Sequencing

Clinical Exome Sequencing