Hamartin

Hamartin, also called tuberous sclerosis complex 1 or TSC1, is a protein in vertebrates that acts as a tumor suppressor. TASC1 is encoded by the eponymous gene "TSC1", which is located on chromosome 9q34.13.

The TSC1 (TSC Complex Subunit 1) gene is a protein-coding gene. It belongs to the tumor suppressor genes. TSC1 codes for the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase-activating protein tuberin. This hamartin-tuberin complex negatively regulates mTORC1 (mammalian target of rapamycin complex 1) signaling. The mTORC1 signaling is an important regulator of anabolic cell growth.

Hamartin also functions as a co-chaperone for Hsp90, inhibiting its ATPase activity. This protein facilitates Hsp90-mediated folding of kinase and non-kinase enzymes including Tsc2, thereby preventing their ubiquitination or proteasomal degradation. Mutations in this gene are associated with tuberous sclerosis.

Hamartin is one of the endogenous neuroprotective molecules. It is known that the mTOR pathway controls cellular responses to hypoxia (Srivastava et al., 2015); the neuroprotective function of hamartin also proceeds through the mTOR pathway(Hadley et al. 2019).

Diseases associated with TSC1 include:

• Tuberous sclerosis
• and
• Isolated focal cortical dysplasia.

TSC1 acts as a co-chaperone for HSP90AA1 and facilitates HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1 (Woodford MR et al. (2017). Increases ATP binding to HSP90AA1 and inhibits ATPase activity of HSP90AA1. Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, creating a reciprocal regulatory mechanism for chaperoning client proteins (Woodford MR et al. 2017). Recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and the ubiquitin ligase HERC1 (Chong-Kopera H et al. (2006).

1. Chong-Kopera H et al. (2006) TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase. J Biol Chem 281:8313-8316.
2. Woodford MR et al (2017) Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients. EMBO J 36:3650-3665.