The c-Abl-MST1 Signaling Pathway Mediates Oxidative Stress-Induced Neuronal Cell Death
Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. The protein kinase MST1 (mammalian Ste20-like kinase 1) plays a major role in oxidative stress-induced cell death in primary mammalian neurons. However, the mechanisms that regulate MST1 in oxidative stress responses remain largely unknown. In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1. Inhibition of c-Abl promotes the degradation of MST1 through C terminus of Hsc70-interacting protein (CHIP)-mediated ubiquitination, and thereby attenuates cell death. Oxidative stress induces the c-Abl-dependent tyrosine phosphorylation of MST1 and increases the interaction between MST1 and FOXO3 (Forkhead box O3), thereby activating the MST1-FOXO signaling pathway, leading to cell death in both primary culture neurons and rat hippocampal neurons. The identification of the c-Abl tyrosine kinase as a novel upstream activator of MST1 suggests that the c-Abl-MST1 signaling cascade plays an important role in cellular responses to oxidative stress.
Available from: jneurosci.org
- "death, was recently reported to play important roles in the regulation of neuronal functions (Lehtinen et al., 2006; Ling et al., 2008; Xiao et al., 2011). The Drosophila homolog of Mst, Hpo, regulates dendrite development (Emoto et al., 2006), whereas an isoform of Mst3 has been implicated in axon outgrowth and regeneration (Irwin et al., 2006; Lorber et al., 2009). "
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ABSTRACT: The radial migration of newborn neurons is critical for the lamination of the cerebral cortex. Proper neuronal migration requires precise and rapid reorganization of the actin and microtubule cytoskeleton. However, the underlying signaling mechanisms controlling cytoskeletal reorganization are not well understood. Here, we show that Mst3, a serine/threonine kinase highly expressed in the developing mouse brain, is essential for radial neuronal migration and final neuronal positioning in the developing mouse neocortex. Mst3 silencing by in utero electroporation perturbed the multipolar-to-bipolar transition of migrating neurons and significantly retards radial migration. Although the kinase activity of Mst3 is essential for its functions in neuronal morphogenesis and migration, it is regulated via its phosphorylation at Ser79 by a serine/threonine kinase, cyclin-dependent kinase 5 (Cdk5). Our results show that Mst3 regulates neuronal migration through modulating the activity of RhoA, a Rho-GTPase critical for actin cytoskeletal reorganization. Mst3 phosphorylates RhoA at Ser26, thereby negatively regulating the GTPase activity of RhoA. Importantly, RhoA knockdown successfully rescues neuronal migration defect in Mst3-knockdown cortices. Our findings collectively suggest that Cdk5-Mst3 signaling regulates neuronal migration via RhoA-dependent actin dynamics.
Available from: Indranil Paul
- "Similarly, under oxidative stress the protein kinase c-Abl phosphorylates another kinase MST1 (mammalian Ste20-like kinase 1) at Tyrosine 433 which in turn accomplishes two roles: first, the event inhibits the degradation of MST1 through CHIP and, second, triggers association between MST1 and FOXO3 (Forkhead box O3), thereby activating the MST1-FOXO signaling, leading to cell death in both primary culture neurons and rat hippocampal neurons . "
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ABSTRACT: The Carboxy-terminus of Hsc70 Interacting Protein (CHIP) is a co-chaperone E3 ligase containing three tandem repeats of tetratricopeptide (TPR) motifs and a C-terminal U-box domain separated by a central charged coiled-coil region. CHIP is known to function as a central quality-control E3 ligase and regulates several proteins involved in a myriad of physiological and pathological processes. Recent studies have highlighted varied regulatory mechanisms operating on the activity of CHIP which is crucial for cellular homeostasis. In this review article, we give a concise account of our current knowledge on the biochemistry and regulation of CHIP.
Available from: Lanfen Chen
- "Yuan’s group further demonstrates that oxidative stress induces the c-Abl-dependent tyrosine phosphorylation of Mst1 and increases the interaction between Mst1 and FOXO3, thereby activating the Mst1-FOXO signaling pathway, leading to cell death in both primary culture neurons and rat hippocampal neurons. These results suggest that c-Abl-Mst-FOXO signaling cascade plays an important role in cellular responses to oxidative stress and might contribute to pathological states including neurodegenerative diseases in the mammalian central nerve system (CNS) [29,30]. Indeed, Mst1 mediated FoxO3 activation in response to β-amyloid (Aβ) has been shown to mediate death of selective neuron in Alzheimer's disease (AD) . "
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ABSTRACT: The Hippo signaling pathway has emerged as a critical regulator for organ size control. The serine/threonine protein kinases Mst1 and Mst2, mammalian homologs of the Hippo kinase from Drosophila, play the central roles in the Hippo pathway controlling the cell proliferation, differentiation, and apoptosis during development. Mst1/2 can be activated by cellular stressors and the activation of Mst1/2 might enforce a feedback stimulation system to regulate oxidant levels through several mechanisms, in which regulation of cellular redox state might represent a tumor suppressor function of Mst1/2. As in Drosophila, murine Mst1/Mst2, in a redundant manner, negatively regulate the Yorkie ortholog YAP in multiple organs, although considerable diversification in the pathway composition and regulation is observed in some of them. Generally, loss of both Mst1 and Mst2 results in hyperproliferation and tumorigenesis that can be largely negated by the reduction or elimination of YAP. The Hippo pathway integrates with other signaling pathways e.g. Wnt and Notch pathways and coordinates with them to impact on the tumor pathogenesis and development. Furthermore, Mst1/2 kinases also act as an important regulator in immune cell activation, adhesion, migration, growth, and apoptosis. This review will focus on the recent updates on those aspects for the roles of Mst1/2 kinases.
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