What is Drosophila telling us about cancer ?

In Drosophila, genetic loss of the tumour suppressor protein Dlg (in dlg mu tants) or p127 (in lgl mutants) leads to loss of epithelial structure and e xcess proliferation in the imaginal discs and brain of the developing larva . These phenotypes show most of the characteristic features of human neopla sia, so study of the gene products may contribute to our understanding of c ancer. Both proteins occur in high molecular-mass complexes in the membrane -associated cytoskeleton, and they both appear to play dual roles as struct ural proteins and active partners in signal transduction. Dlg is a membrane -associated guanylate kinase homolog (MAGUK) found at septate junctions bet ween epithelial cells, as well as at neuromuscular junctions. Specific doma ins of the protein are required for membrane targeting and for localisation in junctions, and for epithelial cell proliferation control; all of these functions are probably mediated through binding to other proteins. Loss of Dlg results in the absence of septate junctions, delocalisation of several proteins including Fasciclin III, Coracle, actin and tubulin, and loss of c ell polarity. p127, although mostly associated with the plasma membrane, is in most cell types also present in the cytoplasm. It shows a dynamic subce llular distribution, and its cytosolic and membrane-associated forms play d istinctive roles by interacting with different binding partners, in particu lar the non-muscle myosin II heavy chain. Defects associated with the lgl t emperature-sensitive allele include loss of the columnar organisation of ep ithelial cells, indicating that p127 contributes to cell structure, presuma bly by stabilising the plasma membrane. In addition to their organising fun ctions, both Dlg and p127 appear to be involved in signal transduction path ways. Study of these genes shows that some proteins play both structural an d functional roles, and that cancer can involve changes in the organisation of signalling pathways in addition to changes in individual pathway compon ents.