Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation

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

doi:10.1172/jci84262

Cited by 50 publications

(50 citation statements)

References 95 publications

(96 reference statements)

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“…Reduced levels of β-Catenin were also observed in both the 621-101 and P6-SMC lines (Fig. 4D), a phenotype recently reported in TSC2-deficient melanocytes (36). Consistent with the female preponderance of LAM, P6-SMCs exhibited pervasive expression of Progesterone Receptor (PR) and Estrogen Receptor alpha (ER-α) (3–6) (Fig.4E), which notably did not appear to change with further TSC2 reduction (Supplementary Fig.…”

Section: Resultssupporting

confidence: 80%

Human Pluripotent Stem Cell–Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis

et al. 2017

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Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here we generated a robust human cell model of LAM by reprogramming TSC2 mutation-bearing fibroblasts from a patient with both Tuberous Sclerosis Complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSCs), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2+/− mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributed to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM which can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM.

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Section: Resultssupporting

confidence: 80%

Human Pluripotent Stem Cell–Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis

et al. 2017

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“…S1C) cells. A recent report showed that mTORC1 activation resulted in feedback inactivation of Akt, leading to reduced GSK3β phosphorylation (pGSK3β) at serine 9 and concomitant loss of β-catenin activation in melanoma cell lines (18). However, mTORC1 activation in MEF cells exerted no effect on pGSK3β (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 97%

mTORC1 signaling suppresses Wnt/β-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level

Zeng

Lü

Zamponi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Wnt/β-catenin signaling plays pivotal roles in cell proliferation and tissue homeostasis by maintaining somatic stem cell functions. The mammalian target of rapamycin (mTOR) signaling functions as an integrative rheostat that orchestrates various cellular and metabolic activities that shape tissue homeostasis. Whether these two fundamental signaling pathways couple to exert physiological functions still remains mysterious. Using a genome-wide CRISPR-Cas9 screening, we discover that mTOR complex 1 (mTORC1) signaling suppresses canonical Wnt/β-catenin signaling. Deficiency in tuberous sclerosis complex 1/2 (TSC1/2), core negative regulators of mTORC1 activity, represses Wnt/β-catenin target gene expression, which can be rescued by RAD001. Mechanistically, mTORC1 signaling regulates the cell surface level of Wnt receptor Frizzled (FZD) in a Dishevelled (DVL)-dependent manner by influencing the association of DVL and clathrin AP-2 adaptor. Sustained mTORC1 activation impairs Wnt/β-catenin signaling and causes loss of stemness in intestinal organoids ex vivo and primitive intestinal progenitors in vivo. Wnt/β-catenin–dependent liver metabolic zonation gene expression program is also down-regulated by mTORC1 activation. Our study provides a paradigm that mTORC1 signaling cell autonomously regulates Wnt/β-catenin pathway to influence stem cell maintenance.

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“…Intriguingly, recent studies on melanocytes, which share a common developmental origin with SCs, revealed parallels between mTORC1 functions in these cell types. Analogous to the differentiation-inhibiting role of mTORC1 in SCs and the negative regulation of Krox20 by mTORC1, mTORC1 hyperactivation in melanocytes impaired melanogenesis, while inhibition of mTORC1 increased levels of MITF, a TF essential for melanin production ( Cao et al, 2017 ; Ho et al, 2011 ). Hence, it will be appealing to explore whether an inhibitory role of mTORC1 activity on cell differentiation is a frequent feature of neural crest-derived cells.…”

Section: Discussionmentioning

confidence: 99%

Dual function of the PI3K-Akt-mTORC1 axis in myelination of the peripheral nervous system

Figlia

Norrmén

Pereira

et al. 2017

eLife

132

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Myelination is a biosynthetically demanding process in which mTORC1, the gatekeeper of anabolism, occupies a privileged regulatory position. We have shown previously that loss of mTORC1 function in Schwann cells (SCs) hampers myelination. Here, we genetically disrupted key inhibitory components upstream of mTORC1, TSC1 or PTEN, in mouse SC development, adult homeostasis, and nerve injury. Surprisingly, the resulting mTORC1 hyperactivity led to markedly delayed onset of both developmental myelination and remyelination after injury. However, if mTORC1 was hyperactivated after myelination onset, radial hypermyelination was observed. At early developmental stages, physiologically high PI3K-Akt-mTORC1 signaling suppresses expression of Krox20 (Egr2), the master regulator of PNS myelination. This effect is mediated by S6K and contributes to control mechanisms that keep SCs in a not-fully differentiated state to ensure proper timing of myelination initiation. An ensuing decline in mTORC1 activity is crucial to allow myelination to start, while remaining mTORC1 activity drives myelin growth.

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Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation

Cited by 50 publications

References 95 publications

Human Pluripotent Stem Cell–Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis

Human Pluripotent Stem Cell–Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis

mTORC1 signaling suppresses Wnt/β-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level

Dual function of the PI3K-Akt-mTORC1 axis in myelination of the peripheral nervous system

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