PKB-Mediated Thr649 Phosphorylation of AS160/TBC1D4 Regulates the R-Wave Amplitude in the Heart.
The Rab GTPase activating protein (RabGAP), AS160/TBC1D4, is an important substrate of protein kinase B (PKB), and regulates insulin-stimulated trafficking of glucose transporter 4. Besides, AS160/TBC1D4 has also been shown to regulate trafficking of many other membrane proteins including FA translocase/CD36 in cardiomyocytes. However, it is not clear whether it plays any role in regulating heart functions in vivo. Here, we found that PKB-mediated phosphorylation of Thr649 on AS160/TBC1D4 represented one of the major PAS-binding signals in the heart in response to insulin. Mutation of Thr649 to a non-phosphorylatable alanine increased the R-wave amplitude in the AS160Thr649Ala knockin mice. However, this knockin mutation did not affect the heart functions under both normal and infarct conditions. Interestingly, myocardial infarction induced the expression of a related RabGAP, TBC1D1, in the infarct zone as well as in the border zone. Together, these data show that the Thr649 phosphorylation of AS160/TBC1D4 plays an important role in the heart's electrical conduction system through regulating the R-wave amplitude.
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210061, China.
Chao
C
Quan
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210061, China.
Bingxian
B
Xie
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210061, China.
Hong Yu
HY
Wang
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210061, China.
Shuai
S
Chen
D000409:Alanine / Q000378:metabolism; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D004562:Electrocardiography; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D006329:Heart Conduction System / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism*
D018955:CD36 Antigens; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; C495693:Slc2a4 protein, mouse; C095906:Tbc1d1 protein, mouse; C505647:Tbc1d4 protein, mouse; D013912:Threonine; D051057:Proto-Oncogene Proteins c-akt; D000409:Alanine