This family includes the hamartin protein which is thought to function as a tumour suppressor. The hamartin protein interacts with the tuberin protein . Tuberous sclerosis complex (TSC) is an autosomal dominant disorder and is characterised by the presence of hamartomas in many organs, such as brain, skin, heart, lung, and kidney. It is caused by mutation in either TSC1 or TSC2 tumour suppressor genes. TSC1 encodes a protein, hamartin, containing two coiled-coil regions, which have been shown to mediate binding to tuberin. The TSC2 gene codes for tuberin .
RTP801, also known as REDD1, is the protein product of a hypoxia-inducible factor 1 (HIF-1)- responsive gene and is thought to be involved in various cellular processes []. Both RTP801 and RTP801-like (REDD2) work downstream of AKT and upstream of TSC2 to inhibit mTOR, a serine/threonine kinase that plays an essential role in cell growth control []. Two members of this family expressed by Drosophila melanogaster, Scylla () and Charybde (), are designated as Hox targets [, ].
Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by a mutation in either the TSC1 or TSC2 tumour suppressor genes. The disease ischaracterised by hamartomas in one or more organs (including brain, skin,heart and kidney) giving rise to a broad phenotypic spectrum (including seizures, mental retardation, renal dysfunction and dermatological abnormalities. TSC2 encodes tuberin, a putative GTPase activatingprotein for rap1 and rab5. The TSC1 gene was recently identified and codesfor hamartin, a novel protein with no significant similarity to tuberin orany other known vertebrate protein []. Hamartin and tuberin have been shown to associate physically in vivo, their interaction being mediated by predicted coiled-coil domains. It is thought that hamartin and tuberin function in the same complex, rather than in separate pathways.Moreover, because oligomerisation of the hamartin C-terminal coiled coildomain is inhibited by the presence of tuberin, it is possible that tuberinacts as a chaperone, preventing hamartin self-aggregation [].Tuberin is a widely expressed 1784-amino-acid protein. Expression of the wild-type gene in TSC2 mutant tumour cells inhibits proliferation andtumorigenicity. This "suppressor"activity is encoded by a functionaldomain in the C terminus that shares similarity with the GTPase activatingprotein Rap1GAP []. It is thought that tuberin functions as a Rab5GAP in vivo to negatively regulate Rab5-GTP activity in endocytosis []. It also acts as a GTPase-activating protein (GAP) for the small GTPase RheB, a direct activator of the protein kinase activity of mTORC1 [, ].
This superfamily represents the C-terminal domain of RTP801 (also known as REDD1), the protein product of a hypoxia-inducible factor 1 (HIF-1)- responsive gene []. It is thought to be involved in various cellular processes []. Both RTP801 and RTP801-like (REDD2) work downstream of AKT and upstream of TSC2 to inhibit mTOR, a serine/threonine kinase that plays an essential role in cell growth control []. Overexpression of RTP801 causes the apoptosis- resistant phenotype in cycling cells, and apoptosis sensitivity in growth arrested cells []. Two members of this superfamily expressed by Drosophila melanogaster, Scylla () and Charybde (), are designated as Hox targets [, ].
Rheb is a Ras-like small GTPase essential for TORC1 activity in mammals []. Rheb activates the protein kinase activity of mTORC1 (rapamycin), and in turn stimulates the phosphorylation of S6K1 and EIF4EBP1 through activation of mTORC1 signaling [, , ]. Rheb alternates between an inactive form bound to GDP and an active form bound to GTP. It is inactivated by TSC1-TSC2 via the GTPase activating protein (GAP) domain of TSC2 []. The mechanism of action of Rheb has been determined from the tertiary structure [].
This SPRY domain is found in the HERC1, a large protein related to chromosome condensation regulator RCC1. It is widely expressed in many tissues, playing an important role in intracellular membrane trafficking in the cytoplasm as well as Golgi apparatus [, ]. It is both a ubiquitin-protein ligase and a guanine nucleotide exchange factor for ARF and Rab family GTPases. Like other HERC proteins, HERC1 also interacts with tuberous sclerosis 2 (TSC2, tuberin), which suppresses cell growth, and results in the destabilization of TSC2 []. HERC1 is essential for neurotransmitter release and neuronal activity [, ]. Mutations in HERC1 lead to syndromic intellectual disability [, ].
