Protein kinase C iota facilitates insulin-induced glucose transport by phosphorylation of soluble nSF attachment protein receptor regulator (SNARE) double C2 domain protein b.

Publisher: Asian Association for the Study of Diabetes and Blackwell Pub. Asia Country of Publication: Japan NLM ID: 101520702 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2040-1124 (Electronic) Linking ISSN: 20401116 NLM ISO Abbreviation: J Diabetes Investig Subsets: MEDLINE

Original Publication: Tokyo : Asian Association for the Study of Diabetes and Blackwell Pub. Asia

Insulin Resistance*; Calcium-Binding Proteins/*physiology ; Glucose/*metabolism ; Glucose Intolerance/*pathology ; Hypoglycemic Agents/*pharmacology ; Insulin/*pharmacology ; Isoenzymes/*metabolism ; Nerve Tissue Proteins/*physiology ; Protein Kinase C/*metabolism; 3T3-L1 Cells ; Adipocytes/cytology ; Adipocytes/drug effects ; Adipocytes/metabolism ; Animals ; Cells, Cultured ; Glucose Intolerance/chemically induced ; Glucose Intolerance/metabolism ; Islets of Langerhans/cytology ; Islets of Langerhans/drug effects ; Islets of Langerhans/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Muscle, Skeletal/cytology ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/metabolism ; Phosphorylation

Aims/introduction: Double C2 domain protein b (DOC2b), one of the synaptotagmins, has been shown to translocate to the plasma membrane, and to initiate membrane-fusion processes of vesicles containing glucose transporter 4 proteins on insulin stimulation. However, the mechanism by which DOC2b is regulated remains unclear. Herein, we identified the upstream regulatory factors of DOC2b in insulin signal transduction. We also examined the role of DOC2b on systemic homeostasis using DOC2b knockout (KO) mice.
Materials and Methods: We first identified DOC2b binding proteins by immunoprecipitation and mutagenesis experiments. Then, DOC2b KO mice were generated by disrupting the first exon of the DOC2b gene. In addition to the histological examination, glucose metabolism was assessed by measuring parameters on glucose/insulin tolerance tests. Insulin-stimulated glucose uptake was also measured using isolated soleus muscle and epididymal adipose tissue.
Results: We identified an isoform of atypical protein kinase C (protein kinase C iota) that can bind to DOC2b and phosphorylates one of the serine residues of DOC2b (S34). This phosphorylation is essential for DOC2b translocation. DOC2b KO mice showed insulin resistance and impaired oral glucose tolerance on insulin and glucose tolerance tests, respectively. Insulin-stimulated glucose uptake was impaired in isolated soleus muscle and epididymal adipose tissues from DOC2b KO mice.
Conclusions: We propose a novel insulin signaling mechanism by which protein kinase C iota phosphorylates DOC2b, leading to glucose transporter 4 vesicle translocation, fusion and facilitation of glucose uptake in response to insulin. The present results also showed DOC2b to play important roles in systemic glucose homeostasis.
(© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

J Diabetes Investig. 2019 May;10(3):591-601. (PMID: 30369065)
Nature. 1995 Aug 17;376(6541):599-602. (PMID: 7637810)
Diabetes. 2012 Oct;61(10):2424-32. (PMID: 22698913)
Diabetologia. 2014 Oct;57(10):2173-82. (PMID: 25005332)
Cell Metab. 2007 Apr;5(4):237-52. (PMID: 17403369)
Diabetes. 2009 Feb;58(2):377-84. (PMID: 19033398)
Science. 2010 Mar 26;327(5973):1614-8. (PMID: 20150444)
Nature. 2006 Dec 14;444(7121):945-8. (PMID: 17167488)
Nature. 1995 Dec 21-28;378(6559):785-9. (PMID: 8524413)
Nature. 2001 Dec 13;414(6865):799-806. (PMID: 11742412)
Biochem Biophys Res Commun. 1995 Dec 26;217(3):1053-61. (PMID: 8554557)
J Biol Chem. 2006 Jun 23;281(25):17466-17473. (PMID: 16644736)
Mol Endocrinol. 2004 Feb;18(2):373-83. (PMID: 14615604)
Endocrinology. 1997 Nov;138(11):4721-31. (PMID: 9348199)
J Cell Biol. 1999 Feb 8;144(3):413-25. (PMID: 9971737)
Nat Rev Mol Cell Biol. 2002 Apr;3(4):267-77. (PMID: 11994746)
Int J Hematol. 2000 Jul;72(1):12-9. (PMID: 10979203)
Mol Cell Biol. 1999 Oct;19(10):6765-74. (PMID: 10490615)
Dev Cell. 2012 Jun 12;22(6):1286-98. (PMID: 22609160)
J Biol Chem. 1997 Jan 24;272(4):2551-8. (PMID: 8999972)
Genome Res. 2003 Oct;13(10):2363-71. (PMID: 14525934)
Science. 1997 Mar 28;275(5308):1927-30. (PMID: 9072969)
Diabetes. 2005 Apr;54(4):1056-63. (PMID: 15793244)
J Biol Chem. 2004 May 28;279(22):23740-7. (PMID: 15033971)
Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):10029-34. (PMID: 16782817)
Biochem Biophys Res Commun. 2009 Jul 10;384(4):461-5. (PMID: 19410553)
Cell. 2011 Oct 28;147(3):666-77. (PMID: 22036572)
J Biol Chem. 1989 Aug 5;264(22):12754-7. (PMID: 2666413)
Adipocyte. 2014 Jan 1;3(1):19-29. (PMID: 24575365)
J Clin Invest. 2007 Aug;117(8):2289-301. (PMID: 17641777)
Cell. 1995 Jun 2;81(5):727-36. (PMID: 7774014)
Mol Cell Biol. 1998 Dec;18(12):6971-82. (PMID: 9819385)
J Biochem. 1996 Sep;120(3):671-6. (PMID: 8902635)
Diabetologia. 2004 Feb;47(2):170-84. (PMID: 14722654)
J Biol Chem. 1997 Nov 28;272(48):30075-82. (PMID: 9374484)

19659235 Japan Society for the Promotion of Science; 24659446 Japan Society for the Promotion of Science; 18659269 Japan Society for the Promotion of Science; 23390080 Japan Society for the Promotion of Science; 15H04849 Japan Society for the Promotion of Science; Takeda Science Foundation

Keywords: Calcium sensor; Glucose transporter 4; Insulin signal

0 (Calcium-Binding Proteins)
0 (Doc2b protein, mouse)
0 (Hypoglycemic Agents)
0 (Insulin)
0 (Isoenzymes)
0 (Nerve Tissue Proteins)
EC 2.7.11.13 (Protein Kinase C)
EC 2.7.11.13 (protein kinase C lambda)
IY9XDZ35W2 (Glucose)

Date Created: 20181029 Date Completed: 20190930 Latest Revision: 20231011

20231011

PMC6497606

10.1111/jdi.12965

30369065