The CMT4B disease-causing proteins MTMR2 and MTMR13/SBF2 regulate AKT signalling.
Bottom Line: 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.
Affiliation: Molecular Cell Biology, Paul Scherrer Institut, Villigen, Switzerland.Show MeSH
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Mentions: Mtmr2 and Mtmr13/Sbf2 can acquire three different structural states in vitro and in vivo which affect the signalling of cell in different ways: (i) as a Mtmr2 dimer, (ii) as a Mtmr13/Sbf2 dimer and (iii) as a Mtmr2// Mtmr13/Sbf2 heterotetramer. Our results indicate, that the concentration, ratios and localization of these two Mtmrs have an important impact in which compartments the receptors are guided. Overexpression of Mtmr2 blocks the degradation of EGFR. Since this effect depends on phosphatase activity, it can either result from (i) the dephosphorylation of PI-3-P to phosphatidylinositol (ii) the dephosphorylation of PI-3,5-P2 or (iii) the production of PI-5-P. PI-3,5-P2 is produced in the endosomal compartment and assembles protein complexes for the trafficking into other subcellular locations of the cell [41, 42]. Vps24 is part of the ESCRT-III complex and one of these adaptors . Previous studies revealed that the knockdown of vps24 with RNAi or the overex-pression of dominant-negative forms of vps24 block the degradation of the EGFR [43, 44]. PI-3,5-P2 is therefore an important metabolite for the degradation of the EGFR and PI-3,5-P2 dephosphorylation by Mtmr2 is one of the ways to interfere with EGFR degradation. PI-5-P is the least characterized phosphoinositide. SNX5 has a PX domain that binds PI-5-P. Interestingly, overexpres-sion of SNX5 prevents the degradation of the EGFR indicating that it guides the EGFR away from lysosomes . Consequently, reduction of PI-3,5-P2 levels and the production of PI-5-P are both possible explanations for the observed block in EGFR degradation. It is therefore reasonable to propose that the phosphatase activity of Mtmrs block downstream pathways depending on PI-3,5-P2 and redirects receptors to pathways depending on PI-5-P (Fig. 6). Overexpression of Mtmr13/Sbf2 can counteract this function of Mtmr2. We have previously described that Mtmr13/Sbf2 exists in double transfected cells in a complex with Mtmr2 or separately . It is therefore not clear if Mtmr13/Sbf2 fulfils this counteracting function in a complex with Mtmr2 or independently.
Affiliation: Molecular Cell Biology, Paul Scherrer Institut, Villigen, Switzerland.