Disease-related myotubularins function in endocytic traffic in Caenorhabditis elegans.
MTM1, MTMR2, and SBF2 belong to a family of proteins called the myotubularins. X-linked myotubular myopathy, a severe congenital disorder characterized by hypotonia and generalized muscle weakness in newborn males, is caused by mutations in MTM1 (Laporte et al., 1996). Charcot-Marie-Tooth types 4B1 and 4B2 are severe demyelinating neuropathies caused by mutations in MTMR2 (Bolino et al., 2000) and SBF2/MTMR13 (Senderek et al., 2003), respectively. Although several myotubularins are known to regulate phosphoinositide-phosphate levels in cells, little is known about the actual cellular process that is defective in patients with these diseases. Mutations in worm MTM-6 and MTM-9, myotubularins belonging to two subgroups, disorganize phosphoinositide 3-phosphate localization and block endocytosis in the coelomocytes of Caenorhabditis elegans. We demonstrate that MTM-6 and MTM-9 function as part of a complex to regulate an endocytic pathway that involves the Arf6 GTPase, and we define protein domains required for MTM-6 activity.
Dang
Hope
H
Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721, USA.
Li
Zhai
Z
Skolnik
Edward Y
EY
Fares
Hanna
H
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D003001:Cloning, Molecular; D004705:Endocytosis / Q000502:physiology*; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D008856:Microscopy, Fluorescence; D009154:Mutation; D010716:Phosphatidylinositols / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D034741:RNA, Small Interfering
D000089982:ADP-Ribosylation Factor 6; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; D008164:Luminescent Proteins; D010716:Phosphatidylinositols; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C483312:phosphoinositide 3-phosphate; D049452:Green Fluorescent Proteins; C501072:MTM-6 protein, C elegans; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C475072:SBF2 protein, human; C483311:mtm-9 protein, C elegans; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human