title: Wnt signalling requires MTM-6 and MTM-9 myotubularin lipid-phosphatase function in Wnt-producing cells.
abstract: Wnt proteins are lipid-modified glycoproteins that have important roles in development, adult tissue homeostasis and disease. Secretion of Wnt proteins from producing cells is mediated by the Wnt-binding protein MIG-14/Wls, which binds Wnt in the Golgi network and transports it to the cell surface for release. It has recently been shown that recycling of MIG-14/Wls from the plasma membrane to the trans-Golgi network is required for efficient Wnt secretion, but the mechanism of this retrograde transport pathway is still poorly understood. In this study, we report the identification of MTM-6 and MTM-9 as novel regulators of MIG-14/Wls trafficking in Caenorhabditis elegans. MTM-6 and MTM-9 are myotubularin lipid phosphatases that function as a complex to dephosphorylate phosphatidylinositol-3-phosphate, a central regulator of endosomal trafficking. We show that mutation of mtm-6 or mtm-9 leads to defects in several Wnt-dependent processes and demonstrate that MTM-6 is required in Wnt-producing cells as part of the MIG-14/Wls-recycling pathway. This function is evolutionarily conserved, as the MTM-6 orthologue DMtm6 is required for Wls stability and Wg secretion in Drosophila. We conclude that regulation of endosomal trafficking by the MTM-6/MTM-9 myotubularin complex is required for the retromer-dependent recycling of MIG-14/Wls and Wnt secretion.
authors.affiliation: Hubrecht Institute, Royal Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marie
authors.initials: M
authors.lastname: Silhankova
authors.forename: Fillip
authors.initials: F
authors.lastname: Port
authors.forename: Martin
authors.initials: M
authors.lastname: Harterink
authors.forename: Konrad
authors.initials: K
authors.lastname: Basler
authors.forename: Hendrik C
authors.initials: HC
authors.lastname: Korswagen
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D004330:Drosophila / Q000201:enzymology; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D047908:Intracellular Signaling Peptides and Proteins; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527888:Mig-14 protein, C elegans; D018129:Phosphatidylinositol Phosphates; D051153:Wnt Proteins; C055525:phosphatidylinositol 3-phosphate; C501072:MTM-6 protein, C elegans; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C483311:mtm-9 protein, C elegans; C099588:myotubularin