title: The TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskeleton.
abstract: Tuberous sclerosis complex, an autosomal dominant disease caused by mutations in either TSC1 or TSC2, is characterized by the development of hamartomas in a variety of organs. The proteins encoded by TSC1 and TSC2, hamartin and tuberin, respectively, associate with each other forming a tight complex. Here we show that hamartin binds the neurofilament light chain and it is possible to recover the hamartin-tuberin complex over the neurofilament light chain rod domain spanning amino acids 93-156 by affinity precipitation. Homologous rod domains in other intermediate filaments such as neurofilament medium chain, alpha-internexin, vimentin, and desmin are not able to bind hamartin. In cultured cortical neurons, hamartin and tuberin co-localize with neurofilament light chain preferentially in the proximal to central growth cone region. Interestingly, in the distal part of the growth cone hamartin overlaps with the ezrin-radixin-moesin family of actin binding proteins, and we have validated the interaction of hamartin with moesin. These results demonstrate that hamartin may anchor neuronal intermediate filaments to the actin cytoskeleton, which may be critical for some of the CNS functions of the hamartin-tuberin complex, and abolishing this through mutations in TSC1 or TSC2 may lead to certain neurological manifestations associated with the disease.
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown 02129, USA.
authors.forename: Luciana A
authors.initials: LA
authors.lastname: Haddad
authors.forename: Nicole
authors.initials: N
authors.lastname: Smith
authors.forename: Mark
authors.initials: M
authors.lastname: Bowser
authors.forename: Yo
authors.initials: Y
authors.lastname: Niida
authors.forename: Vanishree
authors.initials: V
authors.lastname: Murthy
authors.forename: Charo
authors.initials: C
authors.lastname: Gonzalez-Agosti
authors.forename: Vijaya
authors.initials: V
authors.lastname: Ramesh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009154:Mutation; D016900:Neurofilament Proteins / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques
chemical_list: D018076:DNA, Complementary; D016900:Neurofilament Proteins; D011506:Proteins; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C044882:neurofilament protein L; D005982:Glutathione Transferase