title: On the lysosomal degradation of neurofibromin and its phosphorylation in cultured melanocytes.
abstract: Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders in humans. Most of the NF1 gene mutations result in a reduction of the amount of neurofibromin to about 50%. Recently, we found that the level of neurofibromin can be regulated post-translationally through the alteration of its half-life. Here, we investigated whether lysosomes are involved in this post-translational regulation in cultured melanocytes of NF1 patients and controls. When the lysosomal degradation was inhibited by chloroquine, an increase of neurofibromin by a factor of 2 to 3, correlating with an increased half-life, was measured. Incubation with phosphoprotein-phosphatase inhibitors also increased the neurofibromin content in melanocytes. Investigations on phosphorylation of neurofibromin revealed a basal phosphorylation in melanocytes cultured with growth factor-deprived medium that increased upon incubation with the growth stimulators PMA or bFGF. Because both factors are also able to increase the half-life of neurofibromin, we suggest its phosphorylation to be an important step in protecting neurofibromin against specific lysosomal degradation.
authors.affiliation: Abteilung Humangenetik, Universität Ulm, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Kaufmann
authors.forename: I
authors.initials: I
authors.lastname: Junge
authors.forename: B
authors.initials: B
authors.lastname: Bartelt
authors.forename: H
authors.initials: H
authors.lastname: Lattke
authors.forename: R
authors.initials: R
authors.lastname: Müller
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D025542:Neurofibromin 1; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D025542:Neurofibromin 1; D011506:Proteins; D019319:Okadaic Acid; D002738:Chloroquine; D013755:Tetradecanoylphorbol Acetate