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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM055632-12S1
Application #
7940515
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Shapiro, Bert I
Project Start
2009-09-30
Project End
2010-11-30
Budget Start
2009-09-30
Budget End
2010-11-30
Support Year
12
Fiscal Year
2009
Total Cost
$253,744
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Slavi, Nefeli; Toychiev, Abduqodir H; Kosmidis, Stylianos et al. (2018) Suppression of connexin 43 phosphorylation promotes astrocyte survival and vascular regeneration in proliferative retinopathy. Proc Natl Acad Sci U S A 115:E5934-E5943
Solan, Joell L; Lampe, Paul D (2018) Spatio-temporal regulation of connexin43 phosphorylation and gap junction dynamics. Biochim Biophys Acta Biomembr 1860:83-90
Kam, Chen Yuan; Dubash, Adi D; Magistrati, Elisa et al. (2018) Desmoplakin maintains gap junctions by inhibiting Ras/MAPK and lysosomal degradation of connexin-43. J Cell Biol 217:3219-3235
Laird, Dale W; Lampe, Paul D (2018) Therapeutic strategies targeting connexins. Nat Rev Drug Discov :
Laird, Dale W; Naus, Christian C; Lampe, Paul D (2017) SnapShot: Connexins and Disease. Cell 170:1260-1260.e1
Aasen, Trond; Mesnil, Marc; Naus, Christian C et al. (2017) Gap junctions and cancer: communicating for 50 years. Nat Rev Cancer 17:74
Leybaert, Luc; Lampe, Paul D; Dhein, Stefan et al. (2017) Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications. Pharmacol Rev 69:396-478
Jacobsen, Nicole L; Pontifex, Tasha K; Li, Hanjun et al. (2017) Regulation of Cx37 channel and growth-suppressive properties by phosphorylation. J Cell Sci 130:3308-3321
Crassous, Pierre-Antoine; Shu, Ping; Huang, Can et al. (2017) Newly Identified NO-Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function. J Am Heart Assoc 6:
Puebla, Carlos; Cisterna, Bruno A; Salas, Daniela P et al. (2016) Linoleic acid permeabilizes gastric epithelial cells by increasing connexin 43 levels in the cell membrane via a GPR40- and Akt-dependent mechanism. Biochim Biophys Acta 1861:439-48

Showing the most recent 10 out of 79 publications