TSCs
TSC1 and TSC2 have a fundamental roles in cell signalling. The hamartin-tuberin complex (hereafter referred to as TSC1-2) acts as a global regulator and integrator of a range of physiological processes (?GRIPP?) the neurocognitive manifestations of TSC result directly from cell-signalling abnormalities.
TSC signaling pathway
TSC1 and TSC2 receive input from several signalling pathways, including the PI3K?Akt (insulin-signalling) pathway, the ERK1/2 pathway, the p38MAPK?MK2 pathway and the LKB1?AMPK (energy-sensing) pathway, as well as GSK3?. Also, there is probably direct input from signalling in response to hypoxia.
In response to these signals, TSC1?2 acts as a GTPase-activating protein (GAP) for Rheb, which, in turn, regulates mTOR (FRAP1).
Activated mTOR has two main downstream targets, S6K and 4E-BP1. This process activates cell growth and proliferation.
Pathology
Tuberous sclerosis complex (TSC) is a multi-system disorder associated with mutations in the TSC1 (hamartin) or TSC2 (tuberin) genes. The neurocognitive features of TSC show wide variability and have generally been attributed to structural brain abnormalities and/or seizures.
The spectrum of neurodevelopmental abnormalities is caused by the biochemical consequences of individual TSC1 and TSC2 mutations.
Members
TSC1 | TSC2 |
References
de Vries PJ, Howe CJ. The tuberous sclerosis complex proteins?a GRIPP on cognition and neurodevelopment. Trends Mol Med. 2007 Aug;13(8):319-26. PMID: 17632034
Findlay GM, Harrington LS, Lamb RF. TSC1-2 tumour suppressor and regulation of mTOR signalling: linking cell growth and proliferation? Curr Opin Genet Dev. 2005 Feb;15(1):69-76. PMID: 15661536
Henske EP. The genetic basis of kidney cancer: why is tuberous sclerosis complex often overlooked? Curr Mol Med. 2004 Dec;4(8):825-31. PMID: 15579029
Mak BC, Yeung RS. The tuberous sclerosis complex genes in tumor development. Cancer Invest. 2004;22(4):588-603. PMID: 15565817
Yeung RS. Multiple roles of the tuberous sclerosis complex genes. Genes Chromosomes Cancer. 2003 Dec;38(4):368-75. PMID: 14566857