Audhya Lab
Dysregulated cell proliferation underlies all forms of oncogenesis. In particular, chromosomal aberrations sometimes enable a subpopulation of cells to grow in an uncontrolled fashion, leading to tumor formation. Such defects are often associated with changes in cellular signal transduction pathways, such as the Ras-Raf-MEK-ERK kinase cascade, which promotes cell survival and growth. Notably, upregulated ERK activity has been implicated in numerous malignancies, including papillary thyroid carcinoma, pancreatic cancer, colorectal cancer, melanoma, and lung cancer. During the course of our studies, we demonstrated that two oncogenic fusion proteins, TFG-NTRK1 and TFG-ALK, created by distinct chromosomal translocation events, localize to subdomains of the endoplasmic reticulum (sites of COPII vesicle formation) and dramatically upregulate ERK activity. Using phosphoproteomic approaches, we are mapping downstream effectors of TFG-NTRK1 and TFG-ALK that simultaneously drive cell transformation and regulate vesicle secretion. By altering membrane transport in the early secretory pathway, TFG fusion proteins may modulate cargo export, potentially enhancing the secretion of growth factors that help to sustain a rich tumor microenvironment.

Importantly, the Ras-Raf-MEK-ERK signaling cascade is a known effector of several ligand-activated growth factor receptors, including EGFR and Her2. Upon stimulation, these receptors hyperactivate Ras, leading to upregulated ERK signaling. To terminate signaling, the receptor is typically downregulated and sequestered within the lumen of the endosome, a process dependent on the ESCRT machinery. Failure to properly route activated receptors for turnover can lead to constitutive mitogenic signaling and potentially oncogenic transformation. Consistent with this idea, numerous mutations that perturb transport through the endocytic system are also associated with cancer. Thus, our studies of endocytosis and ESCRT function also contribute to a better understanding of the mechanisms that govern the termination of receptor signaling, which is essential for normal development.