STK3 phospho T180
Function
Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation (PubMed:11278283, PubMed:8566796, PubMed:8816758). Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ (PubMed:15688006, PubMed:16930133, PubMed:23972470, PubMed:28087714, PubMed:29063833, PubMed:30622739). Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration (PubMed:15688006, PubMed:16930133, PubMed:23972470, PubMed:28087714). STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation. Phosphorylates NKX2-1 (By similarity). Phosphorylates NEK2 and plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosome, and its ability to phosphorylate CROCC and CEP250 (PubMed:21076410, PubMed:21723128). In conjunction with SAV1, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation (PubMed:21104395). Positively regulates RAF1 activation via suppression of the inhibitory phosphorylation of RAF1 on 'Ser-259' (PubMed:20212043). Phosphorylates MOBKL1A and RASSF2 (PubMed:19525978). Phosphorylates MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38 (PubMed:18328708, PubMed:18362890).
Post-translational modifications
Autophosphorylated on two residues Thr-174 and Thr-180, leading to activation (PubMed:23972470, PubMed:29063833). Phosphorylation at Thr-117 and Thr-384 by PKB/AKT1, leads to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation, and increase in its binding to RAF1. Phosphorylated at Ser-15 by PLK1, leading to activation (PubMed:21723128). When autophosphorylated at Thr-180, recruits STRIPAK complex and promotes PP2A-mediated dephosphorylation and inactivation of STK3 (PubMed:29063833, PubMed:30622739).
Proteolytically cleaved by caspase-3 during apoptosis. Proteolytic cleavage results in kinase activation and nuclear translocation of the truncated form (MST1/N).
Ubiquitinated by TRIM69; leading to its redistribution to the perinuclear cytoskeleton, where it is phosphorylated by PLK1 and subsequently activated.
Sequence Similarities
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.
Tissue Specificity
Expressed at high levels in adult kidney, skeletal and placenta tissues and at very low levels in adult heart, lung and brain tissues.
Cellular localization
- Cytoplasm
- Nucleus
- Cytoplasm
- Cytoskeleton
- Microtubule organizing center
- Centrosome
- The caspase-cleaved form cycles between nucleus and cytoplasm (PubMed:11278283, PubMed:19525978). Phosphorylation at Thr-117 leads to inhibition of nuclear translocation (PubMed:19525978).
Alternative names
KRS1, MST2, STK3, Serine/threonine-protein kinase 3, Mammalian STE20-like protein kinase 2, STE20-like kinase MST2, Serine/threonine-protein kinase Krs-1, MST-2