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2.
Nat Commun ; 10(1): 5630, 2019 12 10.
Article in English | MEDLINE | ID: mdl-31822666

ABSTRACT

The lysosomal calcium channel TRPML1, whose mutations cause the lysosomal storage disorder (LSD) mucolipidosis type IV (MLIV), contributes to upregulate autophagic genes by inducing the nuclear translocation of the transcription factor EB (TFEB). Here we show that TRPML1 activation also induces autophagic vesicle (AV) biogenesis through the generation of phosphatidylinositol 3-phosphate (PI3P) and the recruitment of essential PI3P-binding proteins to the nascent phagophore in a TFEB-independent manner. Thus, TRPML1 activation of phagophore formation requires the calcium-dependent kinase CaMKKß and AMPK, which increase the activation of ULK1 and VPS34 autophagic protein complexes. Consistently, cells from MLIV patients show a reduced recruitment of PI3P-binding proteins to the phagophore during autophagy induction, suggesting that altered AV biogenesis is part of the pathological features of this disease. Together, we show that TRPML1 is a multistep regulator of autophagy that may be targeted for therapeutic purposes to treat LSDs and other autophagic disorders.


Subject(s)
Autophagosomes/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism , Calcium/metabolism , Class III Phosphatidylinositol 3-Kinases/metabolism , Lysosomes/metabolism , Signal Transduction , Transient Receptor Potential Channels/metabolism , Autophagosomes/ultrastructure , Autophagy-Related Protein-1 Homolog/metabolism , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Beclin-1/metabolism , Cell Line , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Models, Biological , Mucolipidoses/metabolism , Phosphatidylinositol Phosphates/metabolism , Phosphorylation , Phosphoserine/metabolism , Transient Receptor Potential Channels/agonists
3.
J Neurosci Res ; 86(5): 1044-52, 2008 Apr.
Article in English | MEDLINE | ID: mdl-17975841

ABSTRACT

Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic factor that activates proliferation, differentiation, and migration of various cell types. Its action is mediated by c-Met, a receptor endowed with tyrosine kinase activity that activates complex signaling cascades and mediates diverse cell responses. Although HGF action was first demonstrated in epithelial cells, expression of HGF and c-Met receptor has also been described in developing and adult mammalian brain. In the developing central nervous system, areas of HGF and c-Met expression are coincident with the migratory pathway of precursor cells. In the present article we report that the interaction between c-Met and HGF/SF in striatal progenitor ST14A cells triggers a signaling cascade that induces modification of cell morphology, with decreased cell-cell interactions and increased cell motility; in particular, we analyzed the reorganization of the actin cytoskeleton and the delocalization of beta-catenin and N-cadherin. The testing of other neurotrophic factors (NGF, BDNF, NT3, and CNTF) showed that the observed modifications were peculiar to HGF. We show that phosphoinositide 3-kinase inhibitor treatment, which blocks cell scattering induced by HGF/SF, does not abolish actin and beta-catenin redistribution. The effects of HGF/SF on primary spinal cord cell cultures were also investigated, and HGF/SF was found to have a possible motogenic effect on these cells. The data reported suggest that HGF could play a role in the early steps of neurogenesis as a motogenic factor.


Subject(s)
Actins/metabolism , Central Nervous System/embryology , Hepatocyte Growth Factor/metabolism , Neurons/metabolism , Stem Cells/metabolism , beta Catenin/metabolism , Animals , Cadherins/metabolism , Cell Adhesion/drug effects , Cell Adhesion/physiology , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Line , Cell Movement/drug effects , Cell Movement/physiology , Cells, Cultured , Central Nervous System/cytology , Central Nervous System/metabolism , Cytoskeleton/metabolism , Enzyme Inhibitors/pharmacology , Hepatocyte Growth Factor/pharmacology , Mice , Neurons/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins c-met/drug effects , Proto-Oncogene Proteins c-met/metabolism , Rats , Stem Cells/drug effects
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