Mechanisms by which TFG functions in protein secretion and oncogenesis

Export of proteins from the endoplasmic reticulum (ER) in COPII-coated vesicles occurs at defined sites, which contain the scaffolding protein Sec16. We identify TFG-1, a new conserved regulator of protein secretion that interacts directly with SEC-16 and controls the export of cargoes from the ER in C. elegans. Hydrodynamic studies indicate that TFG-1 forms hexamers, which facilitate the co-assembly of Sec16 with COPII subunits. Consistent with these findings, TFG-1 depletion leads to a dramatic decline in both SEC-16 and COPII levels at ER exit sites. The amino-terminus of human TFG was identified previously as a fusion partner of two protein kinases, creating a pair of oncogenes. We propose that fusion of these kinases to TFG relocalizes their activities to ER exit sites, where they prematurely phosphorylate substrates during ER export. Our findings provide a mechanism by which translocations involving TFG can result in cellular transformation and oncogenesis.