title: C2 domain-containing phosphoprotein CDP138 regulates GLUT4 insertion into the plasma membrane.
abstract: The protein kinase B(β) (Akt2) pathway is known to mediate insulin-stimulated glucose transport through increasing glucose transporter GLUT4 translocation from intracellular stores to the plasma membrane (PM). Combining quantitative phosphoproteomics with RNAi-based functional analyses, we show that a previously uncharacterized 138 kDa C2 domain-containing phosphoprotein (CDP138) is a substrate for Akt2, and is required for optimal insulin-stimulated glucose transport, GLUT4 translocation, and fusion of GLUT4 vesicles with the PM in live adipocytes. The purified C2 domain is capable of binding Ca(2+) and lipid membranes. CDP138 mutants lacking the Ca(2+)-binding sites in the C2 domain or Akt2 phosphorylation site S197 inhibit insulin-stimulated GLUT4 insertion into the PM, a rate-limiting step of GLUT4 translocation. Interestingly, CDP138 is dynamically associated with the PM and GLUT4-containing vesicles in response to insulin stimulation. Together, these results suggest that CDP138 is a key molecule linking the Akt2 pathway to the regulation of GLUT4 vesicle-PM fusion.
authors: Metabolic Signaling and Disease Program, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
authors: Xiangyang
authors: X
authors: Xie
authors: Zhenwei
authors: Z
authors: Gong
authors: Virginie
authors: V
authors: Mansuy-Aubert
authors: Qiong L
authors: QL
authors: Zhou
authors: Suren A
authors: SA
authors: Tatulian
authors: Daniel
authors: D
authors: Sehrt
authors: Florian
authors: F
authors: Gnad
authors: Laurence M
authors: LM
authors: Brill
authors: Khatereh
authors: K
authors: Motamedchaboki
authors: Yu
authors: Y
authors: Chen
authors: Michael P
authors: MP
authors: Czech
authors: Matthias
authors: M
authors: Mann
authors: Marcus
authors: M
authors: Krüger
authors: Zhen Y
authors: ZY
authors: Jiang
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D020868:Gene Silencing / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D040901:Proteomics / Q000379:methods*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics*; D013379:Substrate Specificity; D022161:Transport Vesicles
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D010455:Peptides; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C495693:Slc2a4 protein, mouse; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium