The loss of tuberin promotes cell invasion through the ß-catenin pathway.
Mutations in the tumor suppressor tuberin (TSC2) are a common factor in the development of lymphangioleiomyomatosis (LAM). LAM is a cystic lung disease that is characterized by the infiltration of smooth muscle-like cells into the pulmonary parenchyma. The mechanism by which the loss of tuberin promotes the development of LAM has yet to be elucidated, although several lines of evidence suggest it is due to the metastasis of tuberin-deficient cells. Here we show that tuberin-null cells become nonadherent and invasive. These nonadherent cells express cleaved forms of β-catenin. In reporter assays, the β-catenin products are transcriptionally active and promote MMP7 expression. Invasion by the tuberin-null cells is mediated by MMP7. Examination of LAM tissues shows the expression of cleaved β-catenin products and MMP7 consistent with a model that tuberin-deficient cells acquire invasive properties through a β-catenin-dependent mechanism, which may underlie the development of LAM.
Barnes
Elizabeth A
EA
University of Washington, Department of Surgery, Seattle, Washington 98195, USA.
Kenerson
Heidi L
HL
Mak
Baldwin C
BC
Yeung
Raymond S
RS
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D003260:Contact Inhibition; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000378:metabolism / Q000473:pathology; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D050505:Mutant Proteins; C000624653:TSC2 protein, human; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D053148:Caspase 3; D020783:Matrix Metalloproteinase 7