The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho

Lamb, Richard F.; Roy, Christian; Diefenbach, Tom J.; Vinters, Harry V.; Johnson, Michael W.; Jay, Daniel G.; Hall, Alan

doi:10.1038/35010550

Cited by 304 publications

(228 citation statements)

References 43 publications

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“…Pathways in which tuberin, the TSC2 gene product, is believed to participate include vesicular trafficking (42) and cell cycle regulation (43,44). Hamartin, the TSC1 gene product, also regulates the cell cycle (45)(46)(47)(48) and affects focal adhesion formation via activation of the GTPase Rho (49). To date, no direct connections between the functions of hamartin and tuberin and the function of the VHL protein, pVHL, have been identified.…”

Section: Discussionmentioning

confidence: 99%

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

et al. 2002

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Tuberous sclerosis complex (TSC) is an autosomaldominant disorder characterized by seizures, mental retardation, autism, and tumors of multiple organs. Renal disease in TSC includes angiomyolipomas, cysts, and renal cell carcinomas. It is known that somatic mutations in the von Hippel Lindau (VHL) tumor suppressor gene occur in most clear cell renal carcinomas. To determine whether TSCassociated clear cell carcinomas also contain VHL mutations, we analyzed six tumors for loss of heterozygosity in the VHL gene region of chromosome 3p and for mutations in the VHL gene. Four of the patients were women between the ages of 34 and 68 years, and two were males under the age of 21 years. The loss of heterozygosity analysis was performed using polymorphic microsatellite markers, and the mutational analysis was performed using direct sequencing. Chromosome 3p loss of heterozygosity was not detected, and no VHL mutations were identified. These findings suggest that mutations in the TSC1 and TSC2 genes lead to clear cell renal carcinogenesis via an alternate pathway not involving VHL mutations.

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Section: Discussionmentioning

confidence: 99%

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

et al. 2002

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“…Hamartin interacts with and may function with tuberin to affect cell proliferation (28), its purported chaperone (29), and has also been shown to interact with an N-terminal peptide sequence common to ERM proteins (10). However, expression profiles of ERM proteins do not entirely correlate with the distribution of hamartin in all human tissues.…”

Section: Discussionmentioning

confidence: 99%

“…The exact role of these interactions-or disruption of them-in disease states is not yet known. In addition to data supporting a functional interaction between hamartin and tuberin (9), recent evidence suggests that hamartin regulates cell adhesion via its interaction with ezrin-radixin-moesin (ERM) proteins and activation of a Rho-mediated signaling pathway (10). Loss of heterozygosity at TSC1 and TSC2 chromosomal regions in TSC-associated hamartomas suggests that both proteins act as tumor suppressors (11,12).…”

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confidence: 99%

Hamartin and Tuberin Expression in Human Tissues

et al. 2001

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Tuberous sclerosis (TSC) is a bigenic autosomal dominant disease caused by mutations in one of two tumor-suppressor genes, TSC1 and TSC2, resulting in benign hamartomas and low grade neoplasms in multiple organs including brain, heart, kidney, and skin. We report the results of an immunohistochemical study of the expression of the TSC gene products, tuberin and hamartin, in multiple tissues obtained at autopsy from 12 non-TSC affected patients ranging in age from 20 weeks gestation to 8 years, and surgical specimens from some organs. Tuberin and hamartin are expressed and are colocalized in most tissues. Contrary to a previous report, immunostaining with our antisera detected hamartin in liver, small and large intestine, prostate, and testes. We did not detect significant developmental differences in tuberin or hamartin expression in comparable tissues from patients of different ages. Although tuberin and hamartin colocalize in most tissues and cell types, we provide data that hamartin is more abundantly expressed than tuberin in cells within some tissues including the distal nephron and a population of cells of the endocrine pancreas. These data support the hypothesis that hamartin and tuberin interact and may function together in many tissues where they are co-expressed, but also suggest that hamartin has a discrete and specialized function in certain cell types.

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“…proteins of the ezrin-radixin-moiesin (ERM) family as well as the small G protein Rho. As reported by Lamb et al, 19 ezrin-radixinmoiesin interaction domain spans residues 881-1084. Importantly, interaction of hamartin with the ERM proteins is required for the activation of Rho by serum or lysophosphatidic acid.…”

Section: Biological Activity and Binding Partnersmentioning

confidence: 68%

Hamartin and tuberin: Working together for tumour suppression

Jóźwiak

2005

Intl Journal of Cancer

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TSC1 and TSC2 are two recently identified tumour suppressor genes encoding hamartin and tuberin, respectively, and involved in pathogenesis of tuberous sclerosis, neurological disorder connected with the development of hamartomas in numerous organ systems, including the brain, kidneys, heart and liver. Both protein products of TSC1 and TSC2 form an intracellular complex exerting GTPase-activating (GAP) activity towards a small G protein, Ras homologue enriched in brain (Rheb). Inhibition of Rheb is important for the regulation of mTOR pathway, while mutation of hamartin or tuberin results in uncontrolled cell cycle progression. Tuberin, possessing the Rheb-GAP domain, is phosphorylated by several kinases that confer the signals of growth factor stimulation or low cellular energy levels. Such a modification of tuberin influences its activity within the complex with hamartin and positively or negatively modulates mTOR-regulated protein translation and cellular proliferation. Current article describes biochemical properties of hamartin and tuberin, their known regulatory phosphorylation sites and binding partners. ' 2005 Wiley-Liss, Inc.

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The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho

Cited by 304 publications

References 43 publications

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

Hamartin and Tuberin Expression in Human Tissues

Hamartin and tuberin: Working together for tumour suppression

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