1. ¹Department of Dermatology, Ghent University Hospital, Ghent, Belgium
2. ²Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
3. ³Department of Molecular Cell Biology, Center for Electron Microscopy, Leiden University Medical Center, Leiden, The Netherlands
4. ⁴Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA

Correspondence: Dr Sofie De Schepper, Department of Dermatology, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium. E-mail: sofie.deschepper@ugent.be

⁵These two authors contributed equally to this work.

Received 19 May 2005; Revised 28 September 2005; Accepted 21 October 2005; Published online 5 January 2006.

Abstract

The neurofibromatosis type 1 (NF1) gene product, neurofibromin, is known to interact with Ras, thereby negatively regulating its growth-promoting function. Although this is a well-established interaction, the discovery of other neurofibromin interacting partners could reveal new functional properties of this large protein. Using yeast two-hybrid analysis against a brain cDNA library, we identified a novel interaction between the amyloid precursor protein and the GTPase activating protein-related domain of neurofibromin. This interaction was further analyzed in human melanocytes and confirmed by immunoprecipitation and colocalization studies. In addition, we observed a colocalization of amyloid precursor protein and neurofibromin with melanosomes. Amyloid precursor protein has been proposed to function as a vesicle cargo receptor for the motor protein kinesin-1 in neurons. This colocalization of amyloid precursor protein and neurofibromin with melanosomes was lost in melanocytes obtained from normal skin of a NF1 patient. We suggest that a complex between amyloid precursor protein, neurofibromin, and melanosomes might be important in melanosome transport, which could shed a new light on the etiopathogenesis of pigment-cell-related manifestations in NF1.