1. TSC1 in Facial Angiofibromas
Rachel Clark

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

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

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

5. 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

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

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

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

9. 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.

10. Other Forms of TSC
Kidney
Brain
Eye

11. 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)