Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation
Juxiang Cao, … , Hans R. Widlund, David J. Kwiatkowski
Juxiang Cao, … , Hans R. Widlund, David J. Kwiatkowski
Published December 5, 2016
Citation Information: J Clin Invest. 2017;127(1):349-364. https://doi.org/10.1172/JCI84262.
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Research Article Dermatology Genetics

Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation

Abstract

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.

Authors

Juxiang Cao, Magdalena E. Tyburczy, Joel Moss, Thomas N. Darling, Hans R. Widlund, David J. Kwiatkowski

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Figure 9

Model of interactions in mTOR signaling in normal and TSC melanocytes.

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Model of interactions in mTOR signaling in normal and TSC melanocytes. (...
(A) In normal melanocytes, there is physiological activation of PI3K and AKT and inactivation of the TSC complex (TSC1/TSC2), leading to mTORC1 activity, but retained AKT activity, which then leads to phosphorylation of GSK3β, reduced β-catenin phosphorylation, nuclear entry of β-catenin, activation of TCF/LEF1 enhancer activity, expression of MITF, and expression of MITF target genes, all of which lead to pigment formation. (B) In TSC hypomelanotic macule melanocytes, there is complete loss of either TSC1 or TSC2, leading to high levels of RHEB-GTP, mTORC1 activation, S6K1/2 activation, inactivation of AKT by several mechanisms, activation of GSK3β, phosphorylation of β-catenin, and reduced levels of nuclear β-catenin, leading to reduced transcription of MITF and reduced pigmentation. For both A and B, arrows indicate activating interactions, while solid lines indicate inhibitory interactions. Dotted lines indicate interactions attenuated in hypomelanotic macule melanocytes; green arrows indicate proteins with enhanced activity, and red arrows indicates those with reduced activity. P, phosphorylation; PRAS40, AKT1 substrate 1; mLST8, mTOR-associated protein, LST8 homolog; mSIN1, mammalian stress–activated protein kinase–interacting protein.