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Hamartin

Domain

The C-terminal putative coiled-coil domain is necessary for interaction with TSC2.

Function

In complex with TSC2, inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (PubMed:12271141, PubMed:28215400). Seems not to be required for TSC2 GAP activity towards RHEB (PubMed:15340059). Implicated as a tumor suppressor. Involved in microtubule-mediated protein transport, but this seems to be due to unregulated mTOR signaling (By similarity). Acts as a co-chaperone for HSP90AA1 facilitating HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1 (PubMed:29127155). Increases ATP binding to HSP90AA1 and inhibits HSP90AA1 ATPase activity (PubMed:29127155). Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (PubMed:29127155). Recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and ubiquitin ligase HERC1 (PubMed:16464865, PubMed:29127155).

Involvement in disease

Tuberous sclerosis 1

TSC1

An autosomal dominant multi-system disorder that affects especially the brain, kidneys, heart, and skin. It is characterized by hamartomas (benign overgrowths predominantly of a cell or tissue type that occurs normally in the organ) and hamartias (developmental abnormalities of tissue combination). Clinical manifestations include epilepsy, learning difficulties, behavioral problems, and skin lesions. Seizures can be intractable and premature death can occur from a variety of disease-associated causes.

None

The disease is caused by variants affecting the gene represented in this entry.

Lymphangioleiomyomatosis

LAM

Progressive and often fatal lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. It affects almost exclusively young women and can occur as an isolated disorder or in association with tuberous sclerosis complex.

None

The disease is caused by variants affecting the gene represented in this entry.

Focal cortical dysplasia 2

FCORD2

A form of focal cortical dysplasia, a malformation of cortical development that results in medically refractory epilepsy in the pediatric population and in adults. FCORD2 is a severe form, with onset usually in childhood, characterized by disrupted cortical lamination and specific cytological abnormalities. It is classified in 2 subtypes: type IIA characterized by dysmorphic neurons and lack of balloon cells; type IIB with dysmorphic neurons and balloon cells.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

Phosphorylation at Ser-505 does not affect interaction with TSC2.

Tissue specificity

Highly expressed in skeletal muscle, followed by heart, brain, placenta, pancreas, lung, liver and kidney. Also expressed in embryonic kidney cells.

Cellular localization

  • Cytoplasm
  • Membrane
  • Peripheral membrane protein
  • At steady state found in association with membranes.

Alternative names

  • Hamartin
  • Tuberous sclerosis 1 protein
  • TSC
  • KIAA0243
  • TSC1

Target type

Proteins

Molecular weight

129767Da