Email updates

Keep up to date with the latest news and content from BMC Biology and BioMed Central.

Journal App

google play app store
Open Access Highly Accessed Research article

scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs

Gregory R Leong1, Karen R Goulding1, Nancy Amin2, Helena E Richardson13 and Anthony M Brumby13*

Author Affiliations

1 Peter MacCallum Cancer Centre, 7 St Andrews Place, East Melbourne, 3002, Victoria, Australia

2 Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004, Victoria, Australia

3 Anatomy and Cell Biology Department, University of Melbourne, Melbourne, 3010, Victoria, Australia

For all author emails, please log on.

BMC Biology 2009, 7:62  doi:10.1186/1741-7007-7-62

Published: 24 September 2009

Abstract

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.

Conclusion

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.