The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho.
Loss of the tumour-suppressor gene TSC1 is responsible for hamartoma development in tuberous sclerosis complex (TSC), which renders several organs susceptible to benign tumours. Hamartin, the protein encoded by TSC1, contains a coiled-coil domain and is expressed in most adult tissues, although its function is unknown. Here we show that hamartin interacts with the ezrin-radixin-moesin (ERM) family of actin-binding proteins. Inhibition of hamartin function in cells containing focal adhesions results in loss of adhesion to the cell substrate, whereas overexpression of hamartin in cells lacking focal adhesions results in activation of the small GTP-binding protein Rho, assembly of actin stress fibres and formation of focal adhesions. Interaction of endogenous hamartin with ERM-family proteins is required for activation of Rho by serum or by lysophosphatidic acid (LPA). Our data indicate that disruption of adhesion to the cell matrix through loss of hamartin may initiate the development of TSC hamartomas and that a Rho-mediated signalling pathway regulating cell adhesion may constitute a rate-limiting step in tumour formation.
Lamb
R F
RF
MRC Laboratory for Molecular Cell Biology and Department of Biochemistry, University College London, UK. r.lamb@ucl.ac.uk
Roy
C
C
Diefenbach
T J
TJ
Vinters
H V
HV
Johnson
M W
MW
Jay
D G
DG
Hall
A
A
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism* / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques; D014471:Umbilical Veins / Q000166:cytology; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D000099149:Ezrin
D000199:Actins; D001798:Blood Proteins; D003598:Cytoskeletal Proteins; D008246:Lysophospholipids; D008565:Membrane Proteins; D008840:Microfilament Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D011506:Proteins; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D020741:rho GTP-Binding Proteins; D000099149:Ezrin; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; C071058:moesin; C071776:radixin