Tuberous sclerosis complex: Linking growth and energy signaling pathways with human disease

Aristotelis Astreinidis, Elizabeth P. Henske

Research output: Contribution to journalReview article

160 Citations (Scopus)

Abstract

The most exciting advances in the tuberous sclerosis complex (TSC) field occurred in 1993 and 1997 with the cloning of the TSC2 and TSC1 genes, respectively, and in 2003 with the identification of Rheb as the target of tuberin's (TSC2) GTPase activating protein (GAP) domain. Rheb has a dual role: it activates mTOR and inactivates B-Raf. Activation of mTOR leads to increased protein synthesis through phosphorylation of p70S6K and 4E-BP1. Upon insulin or growth factor stimulation, tuberin is phosphorylated by several kinases, including AKT/PKB, thereby suppressing its GAP activity and activating mTOR. Phosphorylation of hamartin (TSC1) by CDK1 also negatively regulates the activity of the hamartin/tuberin complex. Despite these biochemical advances, exactly how mutations in TSC1 or TSC2 lead to the clinical manifestations of TSC is far from being understood. Two of the most unusual phenotypes in TSC are the apparent metastasis of benign cells carrying TSC1 and TSC2 mutations, resulting in pulmonary lymphangiomyomatosis, and the ability of cells with TSC1 or TSC2 mutations to differentiate into the separate components of renal angiomyolipomas (vessels, smooth muscle and fat). We will discuss how the TSC signaling pathways are affected by mutations in TSC1 or TSC2, focusing on how these mutations may lead to the renal and pulmonary manifestations of TSC.

Original languageEnglish (US)
Pages (from-to)7475-7481
Number of pages7
JournalOncogene
Volume24
Issue number50
DOIs
StatePublished - Nov 14 2005

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Tuberous Sclerosis
Mutation
GTPase-Activating Proteins
Growth
Phosphorylation
Lymphangioleiomyomatosis
70-kDa Ribosomal Protein S6 Kinases
Kidney
Angiomyolipoma
Lung
Smooth Muscle
Organism Cloning
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Fats
Insulin
Neoplasm Metastasis
Phenotype
Genes
tuberous sclerosis complex 2 protein

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Tuberous sclerosis complex : Linking growth and energy signaling pathways with human disease. / Astreinidis, Aristotelis; Henske, Elizabeth P.

In: Oncogene, Vol. 24, No. 50, 14.11.2005, p. 7475-7481.

Research output: Contribution to journalReview article

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