An Activating Mutation in sos-1 Identifies Its Dbl Domain as a Critical Inhibitor of the Epidermal Growth Factor Receptor Pathway during Caenorhabditis elegans Vulval Development

Proper regulation of receptor tyrosine kinase (RTK)-Ras-mitogen-activated protein kinase (MAPK) signaling pathways is critical for normal development and the prevention of cancer. SOS is a dual-function guanine nucleotide exchange factor (GEF) that catalyzes exchange on Ras and Rac. Although the physiologic role of SOS and its CDC25 domain in RTK-mediated Ras activation is well established, the in vivo function of its Dbl Rac GEF domain is less clear. We have identified a novel gain-of-function missense mutation in the Dbl domain of Caenorhabditis elegans SOS-1 that promotes epidermal growth factor receptor (EGFR) signaling in vivo. Our data indicate that a major developmental function of the Dbl domain is to inhibit EGF-dependent MAPK activation. The amount of inhibition conferred by the Dbl domain is equal to that of established trans-acting inhibitors of the EGFR pathway, including c-Cbl and RasGAP, and more than that of MAPK phosphatase. In conjunction with molecular modeling, our data suggest that the C. elegans mutation, as well as an equivalent mutation in human SOS1, activates the MAPK pathway by disrupting an autoinhibitory function of the Dbl domain on Ras activation. Our work suggests that functionally similar point mutations in humans could directly contribute to disease

Molecular and pathological signatures of epithelial–mesenchymal transitions at the cancer invasion front

Reduction of epithelial cell–cell adhesion via the transcriptional repression of cadherins in combination with the acquisition of mesenchymal properties are key determinants of epithelial–mesenchymal transition (EMT). EMT is associated with early stages of carcinogenesis, cancer invasion and recurrence. Furthermore, the tumor stroma dictates EMT through intensive bidirectional communication. The pathological analysis of EMT signatures is critically, especially to determine the presence of cancer cells at the resection margins of a tumor. When diffusion barriers disappear, EMT markers may be detected in sera from cancer patients. The detection of EMT signatures is not only important for diagnosis but can also be exploited to enhance classical chemotherapy treatments. In conclusion, further detailed understanding of the contextual cues and molecular mediators that control EMT will be required in order to develop diagnostic tools and small molecule inhibitors with potential clinical implications

Transcriptional and Translational Downregulation of Thioredoxin Interacting Protein Is Required for Metabolic Reprogramming during G1

Growth factor signaling drives increased glucose uptake and glycolysis—the Warburg effect—that supports macromolecular synthesis necessary for cell growth and proliferation. Thioredoxin interacting protein (TXNIP), a direct and glucose-induced transcriptional target of MondoA, is a potent negative regulator of glucose uptake and utilization. Thus, TXNIP may inhibit cell growth by restricting substrate availability for macromolecular synthesis. To determine TXNIP’s contribution to metabolic reprogramming, we examined MondoA and TXNIP as cells exit quiescence and enter G1. Serum stimulation of quiescent immortal diploid fibroblasts resulted in an acute upregulation of glucose uptake and glycolysis coinciding with downregulation of TXNIP expression. Ectopic expression of either MondoA or TXNIP restricted cell growth by blocking glucose uptake. Mechanistically, Ras-MAPK and PI3K/Akt signaling inhibit TXNIP translation and MondoA-dependent TXNIP transcription, respectively. We propose that the coordinated downregulation of MondoA transcriptional activity at the TXNIP promoter and inhibition of TXNIP translation are key components of metabolic reprogramming required for cells to exit quiescence