In vertebrates, gap junctions are composed of proteins from the connexin family which contains approximately 20 members in humans. Ions, amino acids, nucleotides, other metabolites and some secondary messengers (e.g., calcium, cAMP, cGMP, IP3) readily pass through gap junctions while macromolecules are excluded. GJC is critically important in many cell processes including control of cell proliferation, embryonic development, cell differentiation and the coordination of a variety of homeostatic cellular functions in quiescent cells. The gap junction protein connexin43 (Cx43) is regulated via phosphorylation and its interactions with other proteins. This proposal focuses on the role that these two regulatory processes play during quiescence and how they change with proliferation. Connexin phosphorylation can modulate the levels of gap junctional communication (GJC). Cx43 is phosphorylated at multiple serine residues found in the cytoplasmic, C-terrninal region of the protein. Extensive evidence indicates that GJC changes during the cell cycle, and we have evidence that cells change their Cx43 phosphorylation as they transition from quiescence through the cell cycle. We hypothesize that Cx43 phosphorylation alters the proteins that interact with Cx43 and can change the kinetics of Cx43 trafficking, assembly, gating, and turnover in a cell cycle stage-specific manner that affects important biological processes such as cell migration and proliferation. The importance of this research is exemplified by the linkage of changes in connexin localization and GJC to the exquisite control of cellular proliferation and migration during wound healing and with a loss of growth control during carcinogenesis. We hypothesize that Cx43 phosphorylation changes are linked to these processes in a way that affects cellular function.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cell Development and Function Integrated Review Group (CDF)
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Shapiro, Bert I
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Fred Hutchinson Cancer Research Center
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