Department of Biomolecular Chemistry, University of Wisconsin-Madison Medical School, 1300 University Avenue, Madison, Wisconsin 53706, USA.
Nat Cell Biol. 2011 May;13(5):550-8. doi: 10.1038/ncb2225. Epub 2011 Apr 10.
Export of proteins from the endoplasmic reticulum in COPII-coated vesicles occurs at defined sites that 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 endoplasmic reticulum in Caenorhabditis elegans. Hydrodynamic studies indicate that TFG-1 forms hexamers that facilitate the co-assembly of SEC-16 with COPII subunits. Consistent with these findings, TFG-1 depletion leads to a marked decline in both SEC-16 and COPII levels at endoplasmic reticulum exit sites. The sequence encoding the amino terminus of human TFG has been previously identified in chromosome translocation events involving two protein kinases, which created a pair of oncogenes. We propose that fusion of these kinases to TFG relocalizes their activities to endoplasmic reticulum exit sites, where they prematurely phosphorylate substrates during endoplasmic reticulum export. Our findings provide a mechanism by which translocations involving TFG can result in cellular transformation and oncogenesis.
内质网中 COPII 被膜小泡的蛋白质输出发生在特定的位点，该位点包含支架蛋白 Sec16。我们鉴定了 TFG-1，它是一种新的保守的蛋白质分泌调节剂，可与 SEC-16 直接相互作用，并控制秀丽隐杆线虫内质网中货物的输出。水动力研究表明，TFG-1 形成六聚体，有助于 SEC-16 与 COPII 亚基的共组装。与这些发现一致，TFG-1 的耗竭导致内质网出口部位的 SEC-16 和 COPII 水平明显下降。先前在涉及两种蛋白激酶的染色体易位事件中已经鉴定出编码人 TFG 氨基末端的序列，这两种蛋白激酶创造了一对癌基因。我们提出，这些激酶与 TFG 的融合将它们的活性重新定位到内质网出口部位，在那里它们在蛋白质输出过程中过早地磷酸化底物。我们的发现提供了一种机制，即涉及 TFG 的易位可导致细胞转化和致癌。
