ADP-ribosylation factor-like GTPase 15 enhances insulin-induced AKT phosphorylation in the IR/IRS1/AKT pathway by interacting with ASAP2 and regulating PDPK1 activity.
Decreased phosphorylation in the insulin signalling pathway is a hallmark of insulin resistance. The causes of this phenomenon are complicated and multifactorial. Recently, genomic analyses have identified ARL15 as a new candidate gene related to diabetes. However, the ARL15 protein function remains unclear. Here, we show that ARL15 is upregulated by insulin stimulation. This effect was impaired in insulin-resistant pathophysiology in TNF-α-treated C2C12 myotubes and in the skeletal muscles of leptin knockout mice. In addition, ARL15 localized to the cytoplasm in the resting state and accumulated in the Golgi apparatus around the nucleus upon insulin stimulation. ARL15 overexpression can enhance the phosphorylation of the key insulin signalling pathway molecules IR, IRS1 and AKT in C2C12 myotubes. Moreover, ARL15 knockdown can also specifically inhibit the phosphorylation of PDPK1 Ser241, thereby reducing PDPK1 activity and its downstream phosphorylation of AKT Thr308. Co-immunoprecipitation assays identified ASAP2 as an ARL15-interacting protein. In conclusion, we have identified that ARL15 acts as an insulin-sensitizing effector molecule to upregulate the phosphorylation of members of the canonical IR/IRS1/PDPK1/AKT insulin pathway by interacting with its GAP ASAP2 and activating PDPK1. This research may provide new insights into GTPase-mediated insulin signalling regulation and facilitate the development of new pharmacotherapeutic targets for insulin sensitization.
Department of Endocrinology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Jie
J
Zhao
Department of Endocrinology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Min
M
Wang
Department of Endocrinology and Nephrology, Emergency Medical Center, Chongqing 400014, China.
Wuquan
W
Deng
Department of Endocrinology, 324th Hospital of the People's Liberation Army (No. 324 Hospital of PLA), Chongqing 400020, China.
Daping
D
Zhong
Department of Endocrinology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Youzhao
Y
Jiang
Department of Endocrinology, 169th Hospital of the People's Liberation Army (No. 169 Hospital of PLA), Hengyang, Hunan Province, 421002, China.
Yong
Y
Liao
Department of Endocrinology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. Electronic address: chenbingcqsyd@163.com.
Bing
B
Chen
Department of Clinical Laboratory, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. Electronic address: xlzhang227@aliyun.com.
Xiaoli
X
Zhang
D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000378:metabolism*; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins; D006056:Golgi Apparatus / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
C000620504:ASAP2 protein, mouse; D020690:GTPase-Activating Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D011972:Receptor, Insulin; D064413:3-Phosphoinositide-Dependent Protein Kinases; D051058:Oncogene Protein v-akt; C578564:Pdpk1 protein, mouse; D020727:ADP-Ribosylation Factors; C000620505:ARL15 protein, mouse
AKT; ARL15; ASAP2; Insulin resistance; PDPK1; Phosphorylation