A tumor-associated beta 1 integrin mutation that abrogates epithelial differentiation control.
SCC4 human keratinocytes are derived from a squamous cell carcinoma of the tongue and undergo very little spontaneous differentiation. Introduction of a wild-type beta 1 integrin subunit into SCC4 cells stimulates differentiation, suggesting either that the cells have a defect in the integrin signaling pathways that control differentiation or that the beta1 subunit itself is defective. Here we describe a heterozygous mutation in the SCC4 beta 1 subunit. The mutation, T188I, maps to the I-like domain. It results in constitutive activation of ligand binding, irrespective of the partner alpha subunit, in solid phase assays with recombinant protein and in living cells. The mutation promotes cell spreading, but not proliferation, motility, or invasiveness. It results in sustained activation of Erk MAPK independent of cell spreading. When introduced into SCC4 keratinocytes, the wild-type beta1 integrin stimulates differentiation, whereas the mutant is inactive. Activation of beta 1 integrins in normal keratinocytes also suppresses differentiation. These results establish, for the first time, mutation as a mechanism by which integrins can contribute to neoplasia, because the degree of differentiation in epithelial cancers is inversely correlated with prognosis. They also provide new insights into how integrins regulate keratinocyte differentiation.
Evans
Richard D
RD
Keratinocyte Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, UK.
Perkins
Vivienne C
VC
Henry
Alistair
A
Stephens
Paul E
PE
Robinson
Martyn K
MK
Watt
Fiona M
FM
D000595:Amino Acid Sequence; D000818:Animals; D002294:Carcinoma, Squamous Cell; D002448:Cell Adhesion / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D002642:Chick Embryo; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017354:Point Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
D019012:Integrin beta1; D008024:Ligands; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D020928:Mitogen-Activated Protein Kinases