Hamartin

Hamartin is a protein encoded by the TSC1 gene in humans. It forms a heterodimer with tuberin, the product of TSC2, to create the hamartin-tuberin complex, a critical regulator of cell growth and proliferation.

The TSC1-TSC2 complex acts as a GTPase-activating protein for Rheb, inhibiting the mTORC1 pathway, thereby restraining protein synthesis and cell growth in response to nutrients, energy status, and growth signals. The complex integrates signals from growth factors, insulin, hypoxia, and cellular energy levels, and influences autophagy and cell size.

Germline or somatic mutations in TSC1 cause tuberous sclerosis complex (TSC), a neurocutaneous syndrome characterized by benign tumors called hamartomas in multiple organs, including the brain, kidneys, heart, and skin. The disease often features cortical tubers and subependymal giant cell astrocytomas and seizures. TSC can also arise from mutations in TSC2, and there is variability in severity depending on the mutation.

Hamartin stabilizes tuberin; phosphorylation by AMPK, AKT, and other kinases modulates the activity and stability of the complex, linking energy status and growth signals to mTORC1 activity.

mTOR inhibitors such as everolimus or sirolimus can reduce the size of TSC-related lesions and are used as a systemic therapy in some patients with TSC. Understanding hamartin and the TSC1-TSC2 complex has broad implications for tumor biology and metabolic signaling.