Phosphorylation of Gap Junction Proteins

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

DESCRIPTION: (provided by applicant) Gap junctional communication is critically [unreadable] important in many cell processes including control of cell proliferation, [unreadable] embryonic development, and cell differentiation. These pathways provide for [unreadable] cell-to-cell diffusion of small molecules (<1000 Da) including ions, [unreadable] metabolites, and second messengers. In vertebrates, gap junctions are composed [unreadable] of proteins from the connexin family, which contains over a dozen members. [unreadable] Channels composed of different connexins can be opened or closed to varying [unreadable] degrees by changes in transjunctional voltage, pH, and phosphorylation. This [unreadable] proposal is focused on connexins 43 (Cx43) and 45 for several reasons; both are [unreadable] known to be phosphorylated on multiple serines, both are positively/negatively [unreadable] regulated by kinase effectors such as TPA, however, they have very different [unreadable] conducting properties and share little sequence homology in the cytoplasmic [unreadable] tail region aside from a series of double serine repeats. This proposal [unreadable] examines the role of phosphorylation in the regulation of these gap junction [unreadable] proteins and the channels that they form. We hypothesize that in addition to [unreadable] effects on gating, phosphorylation is important for the regulation of other [unreadable] aspects of Cx43's "life cycle" (i.e., connexin oligomerization, connexin [unreadable] trafficking, gap junction assembly, and protein turnover). Our specific aims [unreadable] are to (1) determine the phosphorylation events within Cx43 and Cx45, which [unreadable] regulate connexin trafficking, gap junction assembly, gating and turnover in [unreadable] homeostatic cells. (2) Characterize kinases that bind to and regulate connexin [unreadable] function. (3) Determine the cell cycle dependent changes in connexin [unreadable] phosphorylation that allow connexin redistribution during mitosis. We plan to [unreadable] apply our knowledge of connexin phosphorylation and phosphorylation specific [unreadable] probes to the analysis of connexin status in wounded skin and the remodeling of [unreadable] gap junctions during heart disease. [unreadable] [unreadable]