Membrane receptor trafficking is important in cellular homeostasis. Alterations in sorting mechanisms have been linked to various neurodegenerative disorders and cancer. In this regard, we recently found that COMMD1 is involved in regulating endosomal trafficking mechanisms. COMMD1 belongs to a class of proteins that are involved in various physiological functions such as copper homeostasis, inflammation and electrolyte transport. In elucidating the mechanism underlying copper regulation by COMMD1, we found that it regulates trafficking of copper transporter ATP7A by forming a novel complex with two coiled-coil domain containing proteins, CCDC22 and CCDC93. This COMMD/CCDC22/CCDC93 or CCC complex regulates the endosomal trafficking of a number of other cargos. We find that this mediated by regulating the action of retromer, a complex involved in transport of cargos from endosomes to the trans-Golgi network or to plasma membrane. Among CCC interacting partners, we also identified an uncharacterized factor C16orf62, which has homology to the retromer subunit VPS35. Interestingly, recurrent mutations in C16orf62 have been noted in hepatocellular carcinoma (HCC) and preliminary evidence indicates that C16orf62 expression is repressed in a proportion of HCCs. Similar to these findings, previous studies from our laboratory found that COMMD1 expression is frequently repressed in various tumors and this repression promotes tumor invasion. Thus, the central hypothesis of my studies is that the CCC complex regulates the trafficking of important surface receptors that affect the oncogenic process in HCC. Furthermore, I speculate that C16orf62 mutations and repressed expression in HCC likely results in altered surface expression of receptor that have important effects on cancer cells. The project's overall goal is to define the role of C16orf62 in the development of HCC and to address this goal I propose the following specific aims: (1) Define the composition and molecular organization of C16orf62 containing complexes. (2) Identify CCC-regulated protein cargos and define factors that are missorted in HCC. The proposed studies combine molecular and biochemical approaches, and state-of-the-art technologies and includes human liver cancer derived samples for molecular analysis. Altogether, this work will establish a fundamental understanding of the function of the CCC complex and its role in liver cancer.
Proteins are transported to their appropriate destinations by a cellular mechanism. Transport of proteins is crucial for cell function and alterations in this transport leads to disease. The proposed studies will identify novel factors that are involved in the regulation of protein transport and will study their role in liver cancer. Findings from these studies may provide new ideas for treating cancer.
| Miyata, Naoteru; Morris, Lindsey L; Chen, Qing et al. (2018) Microbial Sensing by Intestinal Myeloid Cells Controls Carcinogenesis and Epithelial Differentiation. Cell Rep 24:2342-2355 |
