Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation

• Published in: The Journal of clinical investigation Vol. 127; no. 1; pp. 349 - 364
• Main Authors: Cao, Juxiang, Tyburczy, Magdalena E, Moss, Joel, Darling, Thomas N, Widlund, Hans R, Kwiatkowski, David J
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.01.2017
• Subjects: Adolescent; Adult; Alleles; Analysis; beta Catenin - genetics; beta Catenin - metabolism; Biomedical research; Biopsy; Brain research; Cell division; Cell Line, Tumor; Experiments; Female; Gene expression; Gene mutations; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; Humans; Kinases; Laboratories; Male; Mechanistic Target of Rapamycin Complex 1; Melanins - biosynthesis; Melanins - genetics; Melanocytes - metabolism; Melanocytes - pathology; Melanoma; Microphthalmia-Associated Transcription Factor - genetics; Microphthalmia-Associated Transcription Factor - metabolism; Middle Aged; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Mutation; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Risk factors; Signal Transduction; Skin Pigmentation; Studies; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transcription factors; Tuberous sclerosis; Tuberous Sclerosis - genetics; Tuberous Sclerosis - metabolism; Tuberous Sclerosis - pathology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci84262

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor-suppressor gene syndrome caused by inactivating mutations in either TSC1 or TSC2, and the TSC protein complex is an essential regulator of mTOR complex 1 (mTORC1). Patients with TSC develop hypomelanotic macules (white spots), but the molecular mechanisms underlying their formation are not fully characterized. Using human primary melanocytes and a highly pigmented melanoma cell line, we demonstrate that reduced expression of either TSC1 or TSC2 causes reduced pigmentation through mTORC1 activation, which results in hyperactivation of glycogen synthase kinase 3β (GSK3β), followed by phosphorylation of and loss of β-catenin from the nucleus, thereby reducing expression of microphthalmia-associated transcription factor (MITF), and subsequent reductions in tyrosinase and other genes required for melanogenesis. Genetic suppression or pharmacological inhibition of this signaling cascade at multiple levels restored pigmentation. Importantly, primary melanocytes isolated from hypomelanotic macules from 6 patients with TSC all exhibited reduced TSC2 protein expression, and 1 culture showed biallelic mutation in TSC2, one of which was germline and the second acquired in the melanocytes of the hypomelanotic macule. These findings indicate that the TSC/mTORC1/AKT/GSK3β/β-catenin/MITF axis plays a central role in regulating melanogenesis. Interventions that enhance or diminish mTORC1 activity or other nodes in this pathway in melanocytes could potentially modulate pigment production.