DCAS supports cell polarization and cell-cell adhesion complexes in development

Nadezhda Tikhmyanova

doi:10.17918/00002060

Oncogenes or tumor suppressors have been found to play critical roles in cancer and organismal development. However, It is frequently difficult to assess their developmental roles in humans and other mammals, because of the complexity of signaling pathways. The human Cas protein family has 4 members in mammals (BCAR1/p130Cas, NEDD9/HEF1/Cas-L, EFS/Sin1, and CASS4/HEPL), some of which are known to function as oncogenes in inducing metastasis and providing other growth advantages to tumors. To understand if there is a Cas role in development, we created a new genetic Dcas model in Drosophila, which has only a single Cas family member. Loss of Dcas causes 10% of flies to die as embryos from a prominent morphogenic defect affecting dorsal closure. However, Dcas is an important modulator of the phenotypic severity of mutations affecting integrins (If and mew) and their downstream effectors Fak56D or Src42A. Fak56D-Dcas double mutant embryos were embryonal lethal, and had extensive cell polarity defects, including mislocalization and reduced expression of E-cadherin. Further genetic analysis established that loss of Dcas intensified the embryonal lethal phenotypes of mutations in E-cadherin (Shg) or its signaling partners p120- and [beta]-catenin (Arm). Dcas also specifically inhibits the ability of Shg to localize to cell-cell junctions, influencing cell morphology and polarity. These results support an important role for Cas proteins in cell-cell adhesion signaling in development and suggest that human Cas genes may act as important modifiers in human development. We also performed mammalian genetic studies of the role of NEDD9 in mammary tumor development, and a companion study aimed at identifying proteins governing resistance to EGFR-targeting drugs, which identified NEDD9 as one hit from a screen. We found that loss of NEDD9 delays mammary tumor formation, and that together with BCAR1, NEDD9 contributes to the survival of cells treated with EGFR inhibitors. The molecular mechanisms supporting Cas-dependent tumor growth and drug resistance implicate activation of its mammalian and Drosophila partners FAK and Src, translating our finding from Drosophila to other in vivo systems, and indicating Cas function in fruit fly provides important clues to Cas-dependent regulation of tumor growth and drug resistance.

DCAS supports cell polarization and cell-cell adhesion complexes in development

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DCAS supports cell polarization and cell-cell adhesion complexes in development

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