Disease relevance of Mst1

• Surprisingly, however, Mst1 prevents compensatory cardiac myocyte elongation or hypertrophy despite increased wall stress, thereby obscuring the use of the Frank-Starling mechanism, a fundamental mechanism by which the heart maintains cardiac output in response to increased mechanical load at the single myocyte level [1].
• In vivo, cardiac-specific overexpression of Mst1 in transgenic mice results in activation of caspases, increased apoptosis, and dilated cardiomyopathy [1].
• Furthermore, Mst1 is activated by ischemia/reperfusion in the mouse heart in vivo [1].
• These results show that Mst1 works as both an essential initiator of apoptosis and an inhibitor of hypertrophy in cardiac myocytes, resulting in a previously unrecognized form of cardiomyopathy [1].
• Here we demonstrate that, although MSP activation of STK inhibits NO production by macrophages in response to heat-killed Listeria monocytogenes, STK-deficient mice exhibit increased susceptibility to infection with Listeria [2].

High impact information on Mst1

• Phosphorylation of H2B within Ig variable and switch regions requires AID and may be mediated by the histone kinase Mst1 [3].
• In this study, we show that Mst1 is a prominent myelin basic protein kinase activated by proapoptotic stimuli in cardiac myocytes and that Mst1 causes cardiac myocyte apoptosis in vitro in a kinase activity-dependent manner [1].
• Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy [1].
• The importance of Mst1 in cell death caused by clinically relevant pathologic stimuli is unknown, however [1].
• STK belongs to the hepatocyte growth factor receptor family and was identified as the receptor for macrophage-stimulating protein (MSP) [4].

Chemical compound and disease context of Mst1

• MDHM, a macrophage-stimulatory product of Mycoplasma fermentans, leads to in vitro interleukin-1 (IL-1), IL-6, tumor necrosis factor, and prostaglandin production and is pyrogenic in rabbits [5].

Biological context of Mst1

• The region surrounding the Hgfl locus shows homology of syntenty to band p21 on human chromosome 3 [6].
• The gene coding for hepatocyte growth factor-like protein has been localized to mouse chromosome 9 at a locus (Hgfl) distal to the Trf locus [6].
• Furthermore, we demonstrate that low doses of MSP and Epo stimulation of the expanded cells cooperate to induce the phosphorylation of MAP kinase [7].
• Activation of mammalian sterile 20-like kinase 1 (Mst1) by genotoxic compounds is known to stimulate apoptosis in some cell types [1].
• In this study, we demonstrate that stimulation of murine peritoneal macrophages with MSP results in the RON-dependent up-regulation of arginase, an enzyme associated with alternative activation that competes with iNOS for the substrate L-arginine, the products of which are involved in cell proliferation and matrix synthesis [8].

Anatomical context of Mst1

• Using the MEK inhibitor PD98059, we show that the activation of ERK is required for the enhanced BFU-E formation in response to MSP [7].
• The expanded progenitor cells express STK and respond to MSP in a colony assay [7].
• To evaluate the signals induced by MSP/STK in primary erythroid progenitor cells, we adapted a method for the expansion of murine bone marrow mononuclear cells [7].
• MSP mRNA expression increases with age in sensory neuron targets and decreases in sympathetic targets [9].
• Taken together, these results suggest that MSP may actively suppress cell-mediated immune responses through its ability to down-regulate IL-12 production and thus inhibit classical activation of macrophages [10].

Associations of Mst1 with chemical compounds

• Macrophage stimulating protein (MSP) is a pleiotropic growth factor that signals via the Ron receptor tyrosine kinase [9].
• Consistent with their inhibition of the mevalonate pathway, apoptosis and cleavage of Mst1 kinase induced by alendronate, risedronate, and lovastatin, but not clodronate, are blocked by geranylgeraniol, a precursor of geranylgeranyl diphosphate [11].
• The association is stimulated by MSP or serum and is prevented by wortmannin, an inhibitor of the Akt/PKB (protein serine/threonine kinase B) pathway [12].
• Although epothilone B showed the expected effects on the microtubuli, there was no indication of macrophage stimulatory activity by epothilone B, nor did epothilone B inhibit lipopolysaccharide-mediated nitric oxide release [13].
• The microparticles, consisting of crosslinked starch (1,4-alpha-D-glucan with 1,6-alpha-branches), dextran (1,6-alpha-D-glucan with 1,3-alpha-branches), lichenan (1,3-beta-D-glucan), or mannan (1,6-alpha-D-mannan with 1,2-alpha- and 1,3-alpha-branches), were investigated for their macrophage stimulatory properties [14].

Regulatory relationships of Mst1

• We also show that the ability of MSP to inhibit IL-12 production is independent of IL-10 [10].
• We report that Ron mRNA is expressed by NGF-dependent sensory and sympathetic neurons and that these neurons survive and grow with MSP at different stages of development [9].

Other interactions of Mst1

• In this study we demonstrate that pretreatment of macrophages with MSP before IFN-gamma and LPS results in the complete inhibition of IL-12 production due to suppression of p40 expression [10].
• MSP pretreatment of macrophages resulted in decreased tyrosine phosphorylation of Stat-1 and decreased expression of IFN consensus sequence binding protein in response to inflammatory cytokines [10].
• These results show that MSP is a target-derived neurotrophic factor for subsets of sensory and sympathetic neurons at different times during their development [9].
• Our lab and others have previously shown that macrophage-stimulating protein (MSP), through activation of its receptor RON, negatively regulates NO production in response to IFN-gamma and LPS by inhibiting the expression of inducible NO synthase (iNOS) [8].
• Expression of other genes associated with alternative activation, including scavenger receptor A and IL-1R antagonist, is also up-regulated in MSP-stimulated murine macrophages [8].

Analytical, diagnostic and therapeutic context of Mst1

• We demonstrate in vivo that either administration of exogenous MSP or transplantation of MSP-producing cells at the proximal stump of the resected nerve is sufficient to prevent motoneuron atrophy upon axotomy [15].
• In situ hybridization revealed that MSP mRNA was localized to spermatogonia and spermatocytes in the testis and the epithelium lining the lumen of the epididymis [16].
• Western blotting detected STK protein on resident peritoneal macrophages, a target of MSP, and showed that it was autophosphorylated in cells stimulated by MSP [17].
• Comparison of sodium dodecyl sulfate-polyacrylamide gel electrophoresis and radioautography data for immunoprecipitated plasma and liver extract revealed no evidence for hepatic conversion of pro-MSP to MSP [18].

References