Neurofibromin interacts with the cytoplasmic Dynein Heavy Chain 1 in melanosomes of human melanocytes

Abstract

a b s t r a c tNeurofibromin (NF1) is encoded by the NF1 tumour suppressor gene. Mutations result in a disorder known as Neurofibromatosis Type 1 (NF-1), and patients are often diagnosed due to the presence of unusual pigmentary patterns that include Café au lait macules (CALMs). Little is known about how loss of NF1 results in pigmentary defects in melanocytes. We sought to identify novel NF1 interacting proteins and elucidate the molecular mechanisms underlying the pigmentary defects. The cytoplasmic Dynein Heavy Chain 1 (DHC) was found to interact with NF1 along microtubules in vesicular structures identified to be melanosomes. Our studies suggest that NF1 is involved in melanosomal localization, and that disruptions in NF1-DHC interactions may contribute to the abnormal pigmentary features commonly associated with this debilitating syndrome. Structured summary of protein interactions:NF1 physically interacts with DHC by anti bait coimmunoprecipitation (View interaction)

In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

“…To date, only a few studies have described the consequences of the NF1 gene defect on the size and distribution of melanosomes (32,33). It has been shown that melanocytes from some patients with NF1 contain giant pigment granules known as macromelanosomes in both CALMs and non-CALM-derived melanocytes (34).…”

Pigmented (melanotic) diffuse neurofibroma of the back in neurofibromatosis type 1

“…Schwann cells and melanocytes are derived from the neural crest [ 11 ]. Mutations of the NF1 gene in melanocytes have been described in NF1 patients [ 12 ], [ 13 ]. Ultrastructurally, differences in pigmentation exist between melanin in the skin of NF1 patients and samples of the skin of healthy individuals [ 14 ].…”

Neurofibromin Structure, Functions and Regulation

“…De Sheppers et al (2006) [81] further demonstrated a direct interaction between the neurofibromin GRD and amyloid precursor protein (APP) in melanosomes and APP was previously shown to directly interact with neuronal kinesin-1 and hypothesized to constitute a cargo receptor for kinesin-1 in neurons [139]. Similarly, Arun et al (2013b) [140] further demonstrated an interaction between the neurofibromin TBD domain and the dynein heavy chain (DHC), a component of the dynein motor protein involved in retrograde transport along microtubules, in melanosomes. Overall, these data strongly suggest that neurofibromin plays an important role in the intracellular transport of melanosomes in melanocytes, which could account for the pathological mechanism of CALM (Café Au Lait Macule) formation.…”

“…We have already mentioned that LRPPC and DHC interact with the neurofibromin TBD [140,142], that Ras, Spred1, and APP interact with the neurofibromin GRD [20,76,81], that phospholipids, 5HT6 R , Gβγ and LIMK2 interact with the neurofibromin SecPH domain [50,113,132,136], that FAK, CASK, and syndecans interact with the neurofibromin CTD [61,62,115], that tubulin interacts with the neurofibromin TBD/GRD and CTD [58,[64][65][66], and that kinesin 1 and LAMTOR1 are in the same complex as neurofibromin [130,138].…”