title: Caspase proteolysis of the integrin beta4 subunit disrupts hemidesmosome assembly, promotes apoptosis, and inhibits cell migration.
abstract: Caspases are a conserved family of cell death proteases that cleave intracellular substrates at Asp residues to modify their function and promote apoptosis. In this report we identify the integrin beta4 subunit as a novel caspase substrate using an expression cloning strategy. Together with its alpha6 partner, alpha6beta4 integrin anchors epithelial cells to the basement membrane at specialized adhesive structures known as hemidesmosomes and plays a critical role in diverse epithelial cell functions including cell survival and migration. We show that integrin beta4 is cleaved by caspase-3 and -7 at a conserved Asp residue (Asp(1109)) in vitro and in epithelial cells undergoing apoptosis, resulting in the removal of most of its cytoplasmic tail. Caspase cleavage of integrin beta4 produces two products, 1) a carboxyl-terminal product that is unstable and rapidly degraded by the proteasome and 2) an amino-terminal cleavage product (amino acids 1-1109) that is unable to assemble into mature hemidesmosomes. We also demonstrate that caspase cleavage of integrin beta4 sensitizes epithelial cells to apoptosis and inhibits cell migration. Taken together, we have identified a previously unrecognized proteolytic truncation of integrin beta4 generated by caspases that disrupts key structural and functional properties of epithelial cells and promotes apoptosis.
authors.affiliation: Cell Death Regulation Laboratory, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Werner
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Jose V
authors.initials: JV
authors.lastname: Moyano
authors.forename: Fruma
authors.initials: F
authors.lastname: Yehiely
authors.forename: Jonathan C R
authors.initials: JC
authors.lastname: Jones
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Cryns
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism*; D053179:Caspase 7 / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D004847:Epithelial Cells / Q000201:enzymology*; D022002:Hemidesmosomes / Q000378:metabolism*; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism; D039663:Integrin beta4 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
chemical_list: D039161:Integrin alpha6beta4; D039663:Integrin beta4; D053148:Caspase 3; D053179:Caspase 7; D046988:Proteasome Endopeptidase Complex