TSC1 in Facial Angiofibromas Rachel Clark http://ghr.nlm.nih.gov

The Basics Tuberous Sclerosis Complex (TSC) TSC1 and TSC2 Gene products: hamartin and tuberin Abnormalities in skin, brain, kidney, heart Facial angiofibroma

Location & Expression in the Cell Found mostly in the cytoplasm, possible vesicular localization Plank et al.

Structure of Hamartin 1 transmembrane domain 2 coiled-coil domains Interacts with tuberin Binds to ERM proteins (important for cell adhesion, migration)

Cellular Function Forms heterodimer with TSC2 product, tuberin 3 main functions: Inhibits AKT/mTOR signaling pathway Involved in Wnt/β-catenin pathway Involved in intracellular trafficking GTPase-activating activity of Rab1, Rab5 Manning et al., Harvard University

The mTOR Pathway Mechanism of TSC1/TSC2 Regulation: GTPase Activity Normal mTOR Pathway Inactivating Step

Role of Protein Tumor suppressor Expressed in all tissues, but strongly in heart, brain, kidney Knockout mice -/+  tumors -/-  embryonic death Bissler & Kingswood

Facial Angiofibroma A type of TSC (Tuberous Sclerosis Complex) Hamartomas Penetrance is ~100% Gupta et al.

Mutations that Cause TSC Loss of heterozygosity (LOH) Mutation in either TSC1 or TSC2 Autosomal dominant inheritance Many different types of mutations Yamamoto et al.

Other Forms of TSC Kidney Brain Eye

The Big Picture TSC1 and TSC2, mutations in either  TSC Act as a complex Tumor suppressor Regulate many growth/proliferation pathways, mainly mTOR LOH, Many different mutations possible Mutations cause many diseases (e.g. facial angiofibroma)