title: Regulation of Connexin43 Function and Expression by Tyrosine Kinase 2.
abstract: Connexin43 (Cx43) assembly and degradation, the regulation of electrical and metabolic coupling, as well as modulating the interaction with other proteins, involve phosphorylation. Here, we identified and characterized the biological significance of a novel tyrosine kinase that phosphorylates Cx43, tyrosine kinase 2 (Tyk2). Activation of Tyk2 led to a decrease in Cx43 gap junction communication by increasing the turnover rate of Cx43 from the plasma membrane. Tyk2 directly phosphorylated Cx43 residues Tyr-247 and Tyr-265, leading to indirect phosphorylation on residues Ser-279/Ser-282 (MAPK) and Ser-368 (PKC). Although this phosphorylation pattern is similar to what has been observed following Src activation, the response caused by Tyk2 occurred when Src was inactive in NRK cells. Knockdown of Tyk2 at the permissive temperature (active v-Src) in LA-25 cells decreased Cx43 phosphorylation, indicating that although activation of Tyk2 and v-Src leads to phosphorylation of the same Cx43CT residues, they are not identical in level at each site. Additionally, angiotensin II activation of Tyk2 increased the intracellular protein level of Cx43 via STAT3. These findings indicate that, like Src, Tyk2 can also inhibit gap junction communication by phosphorylating Cx43.
authors.affiliation: From the University of Nebraska Medical Center, Omaha, Nebraska 68105.
authors.forename: Hanjun
authors.initials: H
authors.lastname: Li
authors.affiliation: From the University of Nebraska Medical Center, Omaha, Nebraska 68105.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Spagnol
authors.affiliation: From the University of Nebraska Medical Center, Omaha, Nebraska 68105.
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.affiliation: From the University of Nebraska Medical Center, Omaha, Nebraska 68105.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Stauch
authors.affiliation: From the University of Nebraska Medical Center, Omaha, Nebraska 68105 psorgen@unmc.edu.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Sorgen
mesh_terms: D000818:Animals; D002460:Cell Line; D018031:Connexin 43 / Q000096:biosynthesis* / Q000235:genetics; D017629:Gap Junctions / Q000201:enzymology* / Q000235:genetics; D005786:Gene Expression Regulation; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D051381:Rats; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D018031:Connexin 43; C580592:Gja1 protein, rat; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015688:Oncogene Protein pp60(v-src); D053634:TYK2 Kinase; C499357:Tyk2 protein, rat
keywords: Western blot; cell biology; cell signaling; gap junction; phosphorylation