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Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis.

Neuman NA, Henske EP - EMBO Mol Med (2011)

Bottom Line: The vast majority of research regarding these proteins has focused on mammalian Target of Rapamycin (mTOR), a target of Rheb.Here, we propose that there are clinically relevant functions and targets of TSC1, TSC2 and Rheb, which are independent of mTOR.We present evidence that such non-canonical functions of the TSC-Rheb signalling network exist, propose a standard of evidence for these non-canonical functions, and discuss their potential clinical and therapeutic implications for patients with TSC and lymphangioleiomyomatosis (LAM).

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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Model for TSC-related renal angiomyolipoma developmentAt least two potentially TORC1-independent mechanisms contribute to the development of renal angiomyolipomas from a TSC1- or TSC2- mesenchymal precursor cell. First, faulty cell fate specification leads to a tri-lineage differentiation, resulting in the presence of ectopic immature smooth muscle cells, fat and dysplastic vessels all within a single tumour. As noted in the text, TSC/Rheb-dependent regulation of two relevant differentiation/cell fate specification pathways, Notch and B-Raf, may include non-canonical components. Secondly, loss of TSC1 or TSC2 leads to the upregulation of matrix metalloproteinases such as MMP2 and VEGFA/D, which is at least partially independently of mTORC1 and (in the case of MMP2) Rheb. This may promote blood vessel and/or lymphatics recruitment to the tumour, as well as extravasation of TSC1/TSC2- cells, a mechanism, which may potentially contribute to the development of pulmonary LAM.
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fig02: Model for TSC-related renal angiomyolipoma developmentAt least two potentially TORC1-independent mechanisms contribute to the development of renal angiomyolipomas from a TSC1- or TSC2- mesenchymal precursor cell. First, faulty cell fate specification leads to a tri-lineage differentiation, resulting in the presence of ectopic immature smooth muscle cells, fat and dysplastic vessels all within a single tumour. As noted in the text, TSC/Rheb-dependent regulation of two relevant differentiation/cell fate specification pathways, Notch and B-Raf, may include non-canonical components. Secondly, loss of TSC1 or TSC2 leads to the upregulation of matrix metalloproteinases such as MMP2 and VEGFA/D, which is at least partially independently of mTORC1 and (in the case of MMP2) Rheb. This may promote blood vessel and/or lymphatics recruitment to the tumour, as well as extravasation of TSC1/TSC2- cells, a mechanism, which may potentially contribute to the development of pulmonary LAM.

Mentions: Few, if any, human diseases rival the diversity of clinical manifestations of TSC. TSC can impact nearly every organ system in humans with potentially life-threatening consequences in the brain, heart, lung and kidney (Fig 1). In addition to the development of multiple tumours, most individuals with TSC have seizures during childhood (often with onset in infancy), and about 50% of TSC patients have cognitive defects including autism and intellectual disability. The tumours in TSC are historically classified as hamartomas. Hamartomas are benign focal malformations composed of tissue elements normally found at the site of growth, but developing in a disorganized mass. While some of the lesions in TSC seem to fit this definition, such as cerebral cortical tubers, cardiac rhabdomyomas and epithelial renal cysts, some of the other manifestations of TSC, do not seem to arise from normal tissue elements. For example, renal angiomyolipomas are composed of tri-lineage mesenchymal cells that do not have an obvious relationship to the normal cellular elements of the kidney (Fig 2), and pulmonary LAM cells express smooth muscle and neuronal markers in contrast to the lung epithelium in which they reside. Furthermore, all three lineages within angiomyolipomas arise from a common precursor cell, suggesting that tumours in TSC exhibit cell fate plasticity and, therefore, do not fit the classic definition of a hamartoma. Finally, while the vast majority of tumours in TSC are histologically benign and do not generally metastasize, there are two notable exceptions. First, the smooth muscle-like cells of pulmonary LAM, while histologically benign, are believed to metastasize to the lungs through an as-yet-unknown mechanism. Second, children and adults with TSC can develop renal cell carcinomas, malignant angiomyolipomas and mesenchymal lesions, termed PEComas (Crino et al, 2006; Folpe & Kwiatkowski, 2010; Henske, 2004; Linehan et al, 2010; Yu & Henske, 2010). While these clearly malignant lesions are rare, they underscore the diversity of clinical manifestations of TSC and further distinguish TSC from a true ‘hamartomatous’ disorder.


Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis.

Neuman NA, Henske EP - EMBO Mol Med (2011)

Model for TSC-related renal angiomyolipoma developmentAt least two potentially TORC1-independent mechanisms contribute to the development of renal angiomyolipomas from a TSC1- or TSC2- mesenchymal precursor cell. First, faulty cell fate specification leads to a tri-lineage differentiation, resulting in the presence of ectopic immature smooth muscle cells, fat and dysplastic vessels all within a single tumour. As noted in the text, TSC/Rheb-dependent regulation of two relevant differentiation/cell fate specification pathways, Notch and B-Raf, may include non-canonical components. Secondly, loss of TSC1 or TSC2 leads to the upregulation of matrix metalloproteinases such as MMP2 and VEGFA/D, which is at least partially independently of mTORC1 and (in the case of MMP2) Rheb. This may promote blood vessel and/or lymphatics recruitment to the tumour, as well as extravasation of TSC1/TSC2- cells, a mechanism, which may potentially contribute to the development of pulmonary LAM.
© Copyright Policy
Related In: Results  -  Collection

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fig02: Model for TSC-related renal angiomyolipoma developmentAt least two potentially TORC1-independent mechanisms contribute to the development of renal angiomyolipomas from a TSC1- or TSC2- mesenchymal precursor cell. First, faulty cell fate specification leads to a tri-lineage differentiation, resulting in the presence of ectopic immature smooth muscle cells, fat and dysplastic vessels all within a single tumour. As noted in the text, TSC/Rheb-dependent regulation of two relevant differentiation/cell fate specification pathways, Notch and B-Raf, may include non-canonical components. Secondly, loss of TSC1 or TSC2 leads to the upregulation of matrix metalloproteinases such as MMP2 and VEGFA/D, which is at least partially independently of mTORC1 and (in the case of MMP2) Rheb. This may promote blood vessel and/or lymphatics recruitment to the tumour, as well as extravasation of TSC1/TSC2- cells, a mechanism, which may potentially contribute to the development of pulmonary LAM.
Mentions: Few, if any, human diseases rival the diversity of clinical manifestations of TSC. TSC can impact nearly every organ system in humans with potentially life-threatening consequences in the brain, heart, lung and kidney (Fig 1). In addition to the development of multiple tumours, most individuals with TSC have seizures during childhood (often with onset in infancy), and about 50% of TSC patients have cognitive defects including autism and intellectual disability. The tumours in TSC are historically classified as hamartomas. Hamartomas are benign focal malformations composed of tissue elements normally found at the site of growth, but developing in a disorganized mass. While some of the lesions in TSC seem to fit this definition, such as cerebral cortical tubers, cardiac rhabdomyomas and epithelial renal cysts, some of the other manifestations of TSC, do not seem to arise from normal tissue elements. For example, renal angiomyolipomas are composed of tri-lineage mesenchymal cells that do not have an obvious relationship to the normal cellular elements of the kidney (Fig 2), and pulmonary LAM cells express smooth muscle and neuronal markers in contrast to the lung epithelium in which they reside. Furthermore, all three lineages within angiomyolipomas arise from a common precursor cell, suggesting that tumours in TSC exhibit cell fate plasticity and, therefore, do not fit the classic definition of a hamartoma. Finally, while the vast majority of tumours in TSC are histologically benign and do not generally metastasize, there are two notable exceptions. First, the smooth muscle-like cells of pulmonary LAM, while histologically benign, are believed to metastasize to the lungs through an as-yet-unknown mechanism. Second, children and adults with TSC can develop renal cell carcinomas, malignant angiomyolipomas and mesenchymal lesions, termed PEComas (Crino et al, 2006; Folpe & Kwiatkowski, 2010; Henske, 2004; Linehan et al, 2010; Yu & Henske, 2010). While these clearly malignant lesions are rare, they underscore the diversity of clinical manifestations of TSC and further distinguish TSC from a true ‘hamartomatous’ disorder.

Bottom Line: The vast majority of research regarding these proteins has focused on mammalian Target of Rapamycin (mTOR), a target of Rheb.Here, we propose that there are clinically relevant functions and targets of TSC1, TSC2 and Rheb, which are independent of mTOR.We present evidence that such non-canonical functions of the TSC-Rheb signalling network exist, propose a standard of evidence for these non-canonical functions, and discuss their potential clinical and therapeutic implications for patients with TSC and lymphangioleiomyomatosis (LAM).

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Show MeSH
Related in: MedlinePlus