Fasting and Systemic Insulin Signaling Regulate Phosphorylation of Brain Proteins That Modulate Cell Morphology and Link to Neurological Disorders.
Diabetes is strongly associated with cognitive decline, but the molecular reasons are unknown. We found that fasting and peripheral insulin promote phosphorylation and dephosphorylation, respectively, of specific residues on brain proteins including cytoskeletal regulators such as slit-robo GTPase-activating protein 3 (srGAP3) and microtubule affinity-regulating protein kinases (MARKs), in which deficiency or dysregulation is linked to neurological disorders. Fasting activates protein kinase A (PKA) but not PKB/Akt signaling in the brain, and PKA can phosphorylate the purified srGAP3. The phosphorylation of srGAP3 and MARKs were increased when PKA signaling was activated in primary neurons. Knockdown of PKA decreased the phosphorylation of srGAP3. Furthermore, WAVE1, a protein kinase A-anchoring protein, formed a complex with srGAP3 and PKA in the brain of fasted mice to facilitate the phosphorylation of srGAP3 by PKA. Although brain cells have insulin receptors, our findings are inconsistent with the down-regulation of phosphorylation of target proteins being mediated by insulin signaling within the brain. Rather, our findings infer that systemic insulin, through a yet unknown mechanism, inhibits PKA or protein kinase(s) with similar specificity and/or activates an unknown phosphatase in the brain. Ser(858) of srGAP3 was identified as a key regulatory residue in which phosphorylation by PKA enhanced the GAP activity of srGAP3 toward its substrate, Rac1, in cells, thereby inhibiting the action of this GTPase in cytoskeletal regulation. Our findings reveal novel mechanisms linking peripheral insulin sensitivity with cytoskeletal remodeling in neurons, which may help to explain the association of diabetes with neurological disorders such as Alzheimer disease.
From the State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China.
Min
M
Li
From the State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China.
Chao
C
Quan
the Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom, and.
Rachel
R
Toth
the Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom, and.
David G
DG
Campbell
the Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom c.mackintosh@dundee.ac.uk.
Carol
C
MacKintosh
From the State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China, wanghy@nicemice.cn.
Hong Yu
HY
Wang
From the State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China, schen6@163.com chenshuai@nicemice.cn.
Shuai
S
Chen
D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D005215:Fasting; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009422:Nervous System Diseases / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction
D007328:Insulin; D009419:Nerve Tissue Proteins; D005576:Colforsin
MARKs; brain; cytoskeleton; fasting; insulin resistance; neurodegeneration; protein phosphorylation; srGAP3