Hamartin

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

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

Hamartin also acts 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 an endogenous neuroprotective molecule. It is known that the mTOR signaling pathway controls cellular responses to hypoxia (Srivastava et al., 2015); the neuroprotective function of hamartin also runs via the mTOR signaling pathway (Hadley et al. 2019).

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.