Crosstalk between soluble factors and cell-cell interactions: Implications for cell cycle control and tumor development

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Precise and dynamic control of cell behaviors, including proliferation, adhesion, and migration, is required for proper tissue organization and homeostasis. A key element to understanding how these cellular functions are controlled lies in uncovering the topology of the molecular signaling networks that couple environmental signals to cellular responses. In this study, we have parsed the signaling networks involved in cell cycle regulation and tumor development and uncovered novel mechanisms of crosstalk between soluble factors and cell-cell interactions. Our findings demonstrate that extracellular cues, including the epidermal growth factor (EGF), stimulate proliferative signaling through beta-catenin, an intracellular protein that participates in both cell adhesion at the plasma membrane and transcription of cell cycle genes in the nucleus. In fact, EGF-mediated beta-catenin transcriptional activity is an essential signal for proliferation of normal epithelial cells. Additionally, in a cancer cell system, we discover that EGF cooperates with Wnt 3a, a classical agonist of beta-catenin transcriptional activity, to induce greater signaling than either ligand alone. Notably, EGF and Wnt 3a activate transcription using different sub-cellular pools of beta-catenin. Because hyperactive beta-catenin signaling drives proliferation in cancer, this suggests that attenuation beta-catenin signaling may require different therapeutic strategies for EGF- and Wnt-driven tumors. Since beta-catenin signaling can be antagonized by binding to the cell-cell contact protein E-cadherin at the plasma membrane, proliferative signals mediated by beta-catenin may regulate growth suppression at high density, a property of normal cells that is often lost during tumorigenesis. Indeed, in non-tumorigenic epithelial cells, we demonstrate that E-cadherin is upregulated in contexts where beta-catenin signaling and DNA synthesis are suppressed. Additionally, exogenous E-cadherin suppresses proliferation with a strict requirement for beta-catenin binding. Future studies to test the hypothesis that E-cadherin regulates the growth of normal cells will benefit from a quantitative assay developed to measure E-cadherin:beta-catenin complexes. Such quantitative measurements are likely to be important because contact-mediated growth suppression by E-cadherin is coupled with a density-dependent, ligand-depletion mechanism that concomitantly regulates proliferation. Finally, we demonstrate that EGF and other soluble factors synergistically control cell-cell interactions governing organization of normal epithelial cells into multicellular structures. Notably, this behavior resembles the program initiated during metastatic cancer, thus illustrating the flexibility of the epithelial phenotype even in non-cancerous cells. Together, these studies illustrate how the topology of molecular signaling networks can couple environmental cues including soluble extracellular factors and cell-cell interactions to regulate fundamental cellular functions.