Former Interim Director, PBRC
Researcher, University of Hawai`i Cancer Center
Professor, Department of Cell & Molecular Biology (JABSOM)
University of Michigan, Ph.D. (Pharmacology)
University of Hawaiʻi at Mānoa, B.S. (Biology)
Research in our laboratory is focused on understanding the molecular mechanism(s) that regulate the levels, localization, and function of connexin proteins, which comprise intercellular gap junctions. We are currently investigating the regulatory mechanism involving the interaction of connexin43 (Cx43) with the novel intracellular proteins, CIP75 and CIP85. Both proteins are highly conserved among numerous species, including H. sapiens, M. musculus, D. melanogaster, C. elegans, and S. cerevisiae, and are expressed in a wide variety of human and mouse tissues. We discovered that CIP75 interacts with Cx43 localized predominantly in the endoplasmic reticulum (ER) and mediates Cx43 degradation by the proteasome in an ER-associated degradation process, or ERAD. In contrast, CIP85 interacts with Cx43 at the plasma membrane and appears to trigger the internalization of Cx43, which leads to its degradation in lysosomes. It is evident that both of these processes can result in a common end: diminished levels of Cx43 at the plasma membrane and the subsequent impairment of gap junction function. Significantly, recent analyses of gene expression arrays have revealed that CIP75 and CIP85 may play important roles in either the promotion or inhibition of human colon carcinoma, respectively. Moreover, CIP75 appears to act as an oncogene in promoting the development and progression of neuroblastoma. We discovered that high levels of CIP75 correlated with poor prognosis in this devastating childhood cancer, including poor patient survival, advanced stage 4 disease, and metastasis.
Cochrane, K., Su, V., and Lau, A. F. (2013) The connexin43-interacting protein, CIP85, mediates the internalization of connexin43 from the plasma membrane, Cell Communication and Adhesion, In Press
Su, V., Cochrane, K., and Lau, A. F. (2012) Degradation of connexins through the proteasomal, endolysosomal, and phagolysosomal pathways, Journal of Membrane Biology, 245:389–400.
Su, V. and Lau, A. F. (2012) Ubiquitination, intracellular trafficking, and degradation of connexins. Archives of Biochemistry and Biophysics, 524:16-22.
Dunn, C. A., Su, V., Lau, A. F., and Lampe, P. D. (2012) Activation/Ubiquitination of Akt but not Connexin43 regulates gap junction stability. Journal of Biological Chemistry, 287:2600-7
Su, V., Nakagawa, R., Koval, M., and Lau, A. F. (2010) Ubiquitin-independent proteasomal degradation of ER-localized connexin43 mediated by CIP75. Journal of Biological Chemistry, 285:40979-40990