Scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs.
BACKGROUND
Metastatic neoplasias are characterized by excessive cell proliferation and disruptions to apico-basal cell polarity and tissue architecture. Understanding how alterations in cell polarity can impact upon tumour development is, therefore, a central issue in cancer biology. The Drosophila gene scribble (scrib) encodes a PDZ-domain scaffolding protein that regulates cell polarity and acts as a tumour suppressor in flies. Increasing evidence also implicates the loss of human Scrib in cancer. In this report, we investigate how loss of Scrib promotes epithelial tumourigenesis in Drosophila, both alone and in cooperation with oncogenic mutations.


RESULTS
We find that genetically distinct atypical protein kinase C (aPKC)-dependent and Jun N-terminal kinase (JNK)-dependent alterations in scrib mutants drive epithelial tumourigenesis. First, we show that over-expression of the apical cell polarity determinants Crumbs (Crb) or aPKC induces similar cell morphology defects and over-proliferation phenotypes as scrib loss-of-function. However, the morphological and proliferative defects in scrib mutants are independent of Crb function, and instead can be rescued by a dominant negative (kinase dead) aPKC transgene. Secondly, we demonstrate that loss of Scrib promotes oncogene-mediated transformation through both aPKC and JNK-dependent pathways. JNK normally promotes apoptosis of scrib mutant cells. However, in cooperation with oncogenic activated Ras or Notch signalling, JNK becomes an essential driver of tumour overgrowth and invasion. aPKC-dependent signalling in scrib mutants cooperates with JNK to significantly enhance oncogene-mediated tumour overgrowth.


CONCLUSIONS
These results demonstrate distinct aPKC and JNK-dependent pathways through which loss of Scrib promotes tumourigenesis in Drosophila. This is likely to have a direct relevance to the way in which human Scrib can similarly restrain an oncogene-mediated transformation and, more generally, on how the outcome of oncogenic signalling can be profoundly perturbed by defects in apico-basal epithelial cell polarity.
Peter MacCallum Cancer Centre, Victoria, Australia. greg.leong@petermac.org
Gregory R
GR
Leong
Karen R
KR
Goulding
Nancy
N
Amin
Helena E
HE
Richardson
Anthony M
AM
Brumby
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D016764:Cell Polarity; D049109:Cell Proliferation; D048430:Cell Shape; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology*; D004848:Epithelium / Q000201:enzymology / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism*
D029721:Drosophila Proteins; D008565:Membrane Proteins; D050505:Mutant Proteins; C404683:Scrib protein, Drosophila; C064360:crb protein, Drosophila; C115015:PKC-3 protein; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases