Translational Research Program

Regulation of Intercellular Communication

Principal Investigator: Paul Lampe, PhD

Background: Our ongoing cell/molecular research involves the regulation of gap junction assembly and function. Gap junctions allow diffusion of small molecules (<1000 MW) between adjacent cells via matched cell-to-cell membrane channels. Cell-cell communication via these channels is known to play an important role in the control of cell proliferation, embryonic development, cell differentiation, and the regulation of differentiated function in post-mitotic cells. Vertebrate gap junctions are composed of proteins derived from the connexin gene family, and our results indicate that gap junction formation and degradation are highly regulated via protein kinases at various stages of the assembly process and the cell cycle.  Ongoing studies include determination of the cellular localization of different connexin phosphorylation events and the specific serine substrates that are phosphorylated within connexins. Thus, we attempt to link the activation of specific kinases to phosphorylation on a particular residue within the connexin protein and to connexin function in tissue including skin and heart. Our data indicates that kinases such as PKA, PKC, CK1, cdc2/cyclinB, MAP-K and others regulate specific steps of gap junction protein export, assembly, channel gating and degradation in a cell cycle dependent manner. The overall goal of this project is to determine how phosphorylation of gap junction proteins regulates cell and tissue function and how these processes are affected during wound healing and cancer.

Specific Aims:
1. Utilize targeted approaches to define the effects of phosphorylation on the life cycle of Cx43. 
2. Characterize changes in Cx43 phosphorylation and function in skin and heart in response to conditions such as wounding and hypoxia/ischemia.
3. Investigate the in vivo role of Cx43 phosphorylation in skin, heart, ovary, and eye at different developmental stages using phosphorylation site mutants of Cx43.