title: The CMT4B disease-causing proteins MTMR2 and MTMR13/SBF2 regulate AKT signalling.
abstract: Charcot-Marie-Tooth disease type 4B is caused by mutations in the genes encoding either the lipid phosphatase myotubularin-related protein-2 (MTMR2) or its regulatory binding partner MTMR13/SBF2. Mtmr2 dephosphorylates PI-3-P and PI-3,5-P2 to form phosphatidylinositol and PI-5-P, respectively, while Mtmr13/Sbf2 is an enzymatically inactive member of the myotubularin protein family. We have found altered levels of the critical signalling protein AKT in mouse mutants for Mtmr2 and Mtmr13/Sbf2. Thus, we analysed the influence of Mtmr2 and Mtmr13/Sbf2 on signalling processes. We found that overexpression of Mtmr2 prevents the degradation of the epidermal growth factor receptor (EGFR) and leads to sustained Akt activation whereas Erk activation is not affected. Mtmr13/Sbf2 counteracts the blockage of EGFR degradation without affecting prolonged Akt activation. Our data indicate that Mtmr2 and Mtmr13/Sbf2 play critical roles in the sorting and modulation of cellular signalling which are likely to be disturbed in CMT4B.
authors.affiliation: Molecular Cell Biology, Paul Scherrer Institut, Villigen, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Berger
authors.forename: Kristian
authors.initials: K
authors.lastname: Tersar
authors.forename: Kurt
authors.initials: K
authors.lastname: Ballmer-Hofer
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
mesh_terms: D000818:Animals; D002460:Cell Line; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018129:Phosphatidylinositol Phosphates; C106336:phosphatidylinositol 3,5-diphosphate; C055525:phosphatidylinositol 3-phosphate; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C498717:Mtmr2 protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C527213:Sbf2 protein, mouse