Glucose-regulated and drug-perturbed phosphoproteome reveals molecular mechanisms controlling insulin secretion

TY - JOUR

T1 - Glucose-regulated and drug-perturbed phosphoproteome reveals molecular mechanisms controlling insulin secretion

AU - Sacco, Francesca

AU - Humphrey, Sean J

AU - Cox, Jürgen

AU - Mischnik, Marcel

AU - Schulte, Anke

AU - Klabunde, Thomas

AU - Schäfer, Matthias

AU - Mann, Matthias

PY - 2016/11/14

Y1 - 2016/11/14

N2 - Insulin-secreting beta cells play an essential role in maintaining physiological blood glucose levels, and their dysfunction leads to the development of diabetes. To elucidate the signalling events regulating insulin secretion, we applied a recently developed phosphoproteomics workflow. We quantified the time-resolved phosphoproteome of murine pancreatic cells following their exposure to glucose and in combination with small molecule compounds that promote insulin secretion. The quantitative phosphoproteome of 30,000 sites clustered into three main groups in concordance with the modulation of the three key kinases: PKA, PKC and CK2A. A high-resolution time course revealed key novel regulatory sites, revealing the importance of methyltransferase DNMT3A phosphorylation in the glucose response. Remarkably a significant proportion of these novel regulatory sites is significantly downregulated in diabetic islets. Control of insulin secretion is embedded in an unexpectedly broad and complex range of cellular functions, which are perturbed by drugs in multiple ways.

AB - Insulin-secreting beta cells play an essential role in maintaining physiological blood glucose levels, and their dysfunction leads to the development of diabetes. To elucidate the signalling events regulating insulin secretion, we applied a recently developed phosphoproteomics workflow. We quantified the time-resolved phosphoproteome of murine pancreatic cells following their exposure to glucose and in combination with small molecule compounds that promote insulin secretion. The quantitative phosphoproteome of 30,000 sites clustered into three main groups in concordance with the modulation of the three key kinases: PKA, PKC and CK2A. A high-resolution time course revealed key novel regulatory sites, revealing the importance of methyltransferase DNMT3A phosphorylation in the glucose response. Remarkably a significant proportion of these novel regulatory sites is significantly downregulated in diabetic islets. Control of insulin secretion is embedded in an unexpectedly broad and complex range of cellular functions, which are perturbed by drugs in multiple ways.

KW - Journal Article

U2 - 10.1038/ncomms13250

DO - 10.1038/ncomms13250

M3 - Journal article

C2 - 27841257

SN - 2041-1723

VL - 7

SP - 13250

JO - Nature Communications

JF - Nature Communications

ER -