TGF-? signaling controls cell physiology, proliferation and differentiation, and its deregulation acts prominently in cancer progression and fibrosis. In carcinomas, increased TGF-? signaling promotes an epithelial plasticity response that can progress to epithelial-mesenchymal transition (EMT), which is driven by reprogramming of gene expression and marked by loss of epithelial cell-cell junctions and apical-basal polarity, cytoskeletal reorganization, frontal-rear polarity and increased motility that often enables invasion. Partial or complete EMT, as a result of increased TGF-? signaling, associates with increased cell invasion and cancer dissemination, and with cancer stem cell generation by carcinomas. TGF-? binding to a cell surface complex of two types of transmembrane dual-specificity kinase receptors activates the type I receptor T?RI, which in turn activates Smad signaling, yet also initiates Erk MAPK and PI3K-Akt pathway signaling. Smad-mediated changes in gene expression and Erk MAPK and PI3K-Akt pathway signaling are essential for progression through EMT. Recruitment of the adaptor protein ShcA, which is generated as two functional forms, i.e. p52ShcA and p66ShcA, to the activated T?RI, and phosphorylation of ShcA by T?RI on Tyr initiate TGF-?-induced Erk MAPK activation. However, T?RI phosphorylates ShcA predominantly on Ser, but the role of TGF-?-induced Ser phosphorylation of ShcA is unknown. Dissecting the control of TGF-?-induced EMT, we found that downregulation of ShcA, expressed primarily as p52ShcA, leads to EMT through increased autocrine TGF-?/Smad signaling. Furthermore, p52ShcA competes with Smad3 for binding to T?RI and helps define the distribution of TGF-? receptors between clathrin-associated Smad activating complexes, and caveolar complexes, with p52ShcA recruiting TGF-? receptors to the latter. Thus, through its ability to repress autocrine TGF-?/Smad responses, ShcA protects epithelial cells against EMT, and helps maintain epithelial integrity. We now propose a program aimed at defining the central role of ShcA in balancing the spatial distribution of TGF-? receptor complexes and differential TGF-? signaling responses, the control of ShcA function by TGF-? signaling, and to consequently appreciate its role in controlling epithelial plasticity, cell invason, cancer stem cell generation and cancer progression, through its control of TGF-? signaling. Toward these goals, we propose (1) to define the roles of p52ShcA and p66ShcA in the differential distribution and signaling of TGF-? receptors, and T?RI stability and sumoylation, () to define the roles of ShcA Ser phosphorylation in TGF-?-induced signaling responses, (3) to study the role of ShcA in the regulation of epithelial plasticity, cell invasion, cancer stem cell properties and tumor progression by TGF-? signaling. Our results will help understand the role of ShcA in the control of TGF-? signaling, cancer cell behavior and cancer progression, which may lead to approaches to stabilize the epithelial phenotype and prevent epithelial plasticity responses that enable cancer progression and dissemination.
Most cancers derive from epithelial cells, i.e. those cells that line the surfaces of organs in our body. For these cancers, called carcinomas, to become deadly, they have to invade surrounding tissues and disseminate throughout the body, thus requiring the cells to behave more invasive than they normally do. Over the years, we have learned that the response of cancer cells to a secreted protein, named TGF-beta, is of key importance in rendering cancer cells invasive, and that another adaptor protein, named ShcA, plays a central role in controlling the activities of TGF-beta. We request funding to continue our research aimed at understanding the role of ShcA, both in the control of the TGF-beta activities, and the control of cancer cell behavior. This is particularly important in light of our findings tht ShcA may control cancer cell invasion and dissemination.
| Muthusamy, Baby Periyanayaki; Budi, Erine H; Katsuno, Yoko et al. (2015) ShcA Protects against Epithelial-Mesenchymal Transition through Compartmentalized Inhibition of TGF-?-Induced Smad Activation. PLoS Biol 13:e1002325 |
