MSc Exit Seminar – Victoria Yan (Tepass lab)

MSc Exit Seminar

Tuesday September 6^th, 3:10 pm – Ramsay Wright Building, Rm. 432

Victoria Yan (Tepass lab)

“Drosophila α-Catenin regulates growth and EMT”

Abstract

α-catenin (Drosophila α-Catenin/α-Cat) is a linker between the cadherin-catenin complex and the actomyosin cytoskeleton at adherens junctions (AJs) in epithelial cells. The mammalian homologue αE-catenin is a tumour suppressor. Previous studies in mouse knockout skin cells showed a growth suppressive role for αE-catenin, although the underlying molecular mechanism is poorly defined. Whether α-catenin is involved in growth regulation at the AJs or as a cytoplasmic factor remains unclear. α-Cat is mechanosensitive and can undergo a conformational change upon actomyosin contractions to recruit α-Cat binding partners. The function of α-Cat’s mechanosensing is currently not understood. I investigated the role of Drosophila α-Cat in proliferation, and whether α-Cat acts as a mechanosensor at the AJs to regulate Hippo signaling. Using mosaic analysis and tissue-wide RNAi knockdown (KD) in the Drosophila wing disc epithelium, I showed that α-Cat has a dosage-dependent effect on epithelial integrity, proliferation and cell survival, which has allowed us to uncouple α-Cat’s functions in growth regulation and adhesion.  α-Cat null cells undergo epithelial to mesenchymal transition (EMT). Intermediate loss of α-Cat resulted in both autonomous and non-autonomous overgrowth. Cells depleted of α-Cat KD activate JNK signaling and upregulate Yorkie activity. Proliferation of WT cells adjacent to α-Cat KD cells is also enhanced through non-autonomous upregulation of Yorkie activity. To determine whether α-Cat regulates growth at the AJs, I tested the effects of DE-cadherin KD, and identified dosage-dependent defects similar to that of α-Cat RNAi KD, which suggests that α-Cat and DE-cadherin regulate proliferation together at the AJs. Additionally, α-Cat fused to DE-cadherin can rescue proliferation defects in α-Cat KD cells, indicating that a pool of cytosolic α-Cat is not required in growth regulation. Moreover, I showed that the mechanosensitive mid­­­dle region of α-Cat is dispensable for α-Cat’s function in adhesion and proliferation control. My work identified a novel role for α-Cat as a growth regulator at the AJs, in addition to adhesion. This work will stimulate future investigations into how the α-Cat-centered protein network contributes to growth regulation in normal development as well as cancer progression.

Ramsay Wright is a wheelchair accessible building.