Disease relevance of STK3

• Downregulation of MST2 by siRNA reverts the apoptosis hypersensitivity of Raf-1(-/-) mouse fibroblasts [1].
• We applied Affymetrix Human Genome U95Av2 oligonucleotide microarrays representing approximately 12,000 genes to generate the expression profiles of the CCSST cell lines GG-62, DTC-1, KAO, MST2, MST3, and Su-CC-S1 in comparison with 8 neuroblastoma, 7 Ewing tumor, and 6 osteosarcoma cell lines [2].
• Mice (C57BL) succumbed to cultured B16 melanoma cells i.p. with reproducible kinetics and an MST2 of about 26 days [3].

High impact information on STK3

• We have examined the role of caspase-mediated cleavage of the Ste20-like kinases, mammalian sterile 20-like 1 and 2 (Mst1/Mst2), in the mechanism of human eosinophil and neutrophil apoptosis [4].
• Recently, we showed that Raf-1 kinase sequesters and inhibits MST2 and that this event is critical for Raf-mediated cell survival [5].
• As shown previously for apoptosis induced by Ki-Ras(G12V), CNK1-induced apoptosis is suppressed by a dominant inhibitor of the mammalian sterile 20 kinases 1 and (MST1/MST2) [6].
• Mammalian STE20-like kinase 2 (MST2), a member of the STE20-like kinase family, has been shown in previous studies to undergo proteolytic activation by caspase-3 during cell apoptosis [7].
• A few studies have also implicated protein phosphorylation reactions in MST2 regulation [7].

Biological context of STK3

• Cell transfection studies using mutant MST2 constructs indicate that MST2 depends on the autophosphorylation of a unique threonine residue, Thr(180), for kinase activity [7].
• We show that MST1 and MST2 bind at the base and at the tip of the central loop of the toxin, respectively, however, only MST2 actually overlaps the acetylcholine receptor binding site [8].
• Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1 [9].
• Raf-1 prevents dimerization and phosphorylation of the activation loop of MST2 independently of its protein kinase activity [9].
• The role of Krs1 in cell cycle arrest [10].

Anatomical context of STK3

• In contrast, neutrophil apoptosis occurs independently of Mst1 and Mst2 but instead is correlated with the activation of an as-yet-unidentified 34-kd MBPK [4].
• On the other hand, the endogenous full-length MST2 from rat thymus or from proliferating cells is mainly unphosphorylated whereas the caspase-3-truncated endogenous MST2 from apoptotic cells is highly phosphorylated [7].
• Accordingly, we show that the mRNA and protein of the melanocyte-specific isoform of Mitf (Mitf-M) are present in several cultured CCS cell lines (Su-ccs-1, DTC1, Kao, MST-1, MST-2 and MST-3) [11].

Associations of STK3 with chemical compounds

• MST2, therefore, mimicks, at least partially, the site by which the nicotinic acetylcholine receptor recognizes a long-chain neurotoxin [8].
• An in vitro kinase assay indicates that MST2 can phosphorylate an exogenous substrate, as well as itself, and phospho-amino-acid analysis indicates that it is a serine/threonine protein kinase [12].
• Borderline hypertensive but otherwise healthy 21-year-old men (n = 18) underwent 5 min of mental arithmetic stress testing (MST-1) before and at the end of 120 min of isoglycemic hyperinsulinemic glucose clamp (MST-2) with infusion rates of glucose and insulin kept constant [13].
• The hKRS peptide also bound to DNA and polyphosphate; however, the apparent DNA-binding constants decreased at increasing concentrations of Mg(2+) [14].
• We now show that MST2 also recognizes (-) nicotine, an agonist of AcChoR [15].

Regulatory relationships of STK3

• The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1 [16].

Other interactions of STK3

• Both are expressed predominantly as a longer (Nore1A/RASSF1A) and/or shorter (Nore1B/RASSF1C) polypeptide; all four polypeptides contain a Ras-association domain and bind, through their conserved carboxytermini, the proapoptotic protein kinases MST1 and MST2 [17].
• The full-length phospho-MST2 is rapidly dephosphorylated by protein phosphatase 1 or protein phosphatase 2A whereas the truncated MST2 is remarkably resistant to the dephosphorylation [7].
• In the first series (n = 18) the subjects were exposed to a 5-min mental arithmetic stress test prior to (MST-1) and at the end of (MST-2) 120 min of hyperinsulinemic glucose clamp [18].

Analytical, diagnostic and therapeutic context of STK3

• The modified step test two (MST2) was similar to our initial MST1, except that the sandbags added every 3 min were not fixed at 1 kg but were also incremental (1, 2, 3 and 4 kg) [19].
• The ability of the hKRS peptide to adopt alpha-helical conformation was demonstrated by NMR and circular dichroism [14].

References