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(Received for publication, November 20, 1996, and in revised form, January 16, 1997)
From the Divisions of Medical and § Basic Sciences,
Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111
The tuberous sclerosis complex 2 (TSC2) is a tumor suppressor gene that plays a causative
role in the autosomal dominant syndrome of tuberous sclerosis. The
latter is characterized by the development of hamartomas and occasional
malignancies. Expression of the wild-type gene in TSC2
mutant tumor cells inhibits proliferation and tumorigenicity. This
"suppressor" activity is encoded by functional domain(s) in the C
terminus that contains homology to Rap1GAP. Using a yeast two-hybrid
assay to identify proteins that interact with the C-terminal domain of
tuberin, the product of TSC2, a cytosolic factor,
rabaptin-5, was found to associate with a distinct domain lying
adjacent to the TSC2 GAP homology region. Rabaptin-5 also
binds the active form of GTPase Rab5. Immune complexes of native
tuberin, as well as recombinant protein, possessed activity to
stimulate GTP hydrolysis of Rab5. Tuberin GAP activity was specific for
Rab5 and showed no cross-reactivity with Rab3a or Rab6. Cells lacking
tuberin possessed minimal Rab5GAP activity and were associated with an increased uptake of horseradish peroxidase. Re-expression of tuberin in
TSC2 mutant cells reduced the rate of fluid-phase
endocytosis. These findings suggest that tuberin functions as a Rab5GAP
in vivo to negatively regulate Rab5-GTP activity in
endocytosis.
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