ICA512 signaling enhances pancreatic beta-cell proliferation by regulating cyclins D through STATs.
Changes in metabolic demands dynamically regulate the total mass of adult pancreatic beta-cells to adjust insulin secretion and preserve glucose homeostasis. Glucose itself is a major regulator of beta-cell proliferation by inducing insulin secretion and activating beta-cell insulin receptors. Here, we show that islet cell autoantigen 512 (ICA512)/IA-2, an intrinsic tyrosine phosphatase-like protein of the secretory granules, activates a complementary pathway for beta-cell proliferation. On granule exocytosis, the ICA512 cytoplasmic domain is cleaved and the resulting cytosolic fragment (ICA512-CCF) moves into the nucleus where it enhances the levels of phosphorylated STAT5 and STAT3, thereby inducing insulin gene transcription and granule biogenesis. We now show that knockdown of ICA512 decreases cyclin D1 levels and proliferation of insulinoma INS-1 cells, whereas beta-cell regeneration is reduced in partially pancreatectomized ICA512-/- mice. Conversely, overexpression of ICA512-CCF increases both cyclin D1 and D2 levels and INS-1 cell proliferation. Up-regulation of cyclin D1 and D2 by ICA512-CCF is affected by knockdown of STAT3 and STAT5, respectively, whereas it does not require insulin signaling. These results identify ICA512 as a regulator of cyclins D and beta-cell proliferation through STATs and may have implication for diabetes therapy.
Mziaut
Hassan
H
Department of Experimental Diabetology, Center for Regenerative Therapies Dresden, School of Medicine, Dresden University of Technology, 01307 Dresden, Germany.
Kersting
Stephan
S
Knoch
Klaus-Peter
KP
Fan
Wan-Hung
WH
Trajkovski
Mirko
M
Erdmann
Katja
K
Bergert
Hendrik
H
Ehehalt
Florian
F
Saeger
Hans-Detlev
HD
Solimena
Michele
M
D000818:Animals; D049109:Cell Proliferation; D056741:Cyclin D; D056742:Cyclin D2; D016213:Cyclins / Q000096:biosynthesis*; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D051381:Rats; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000378:metabolism / Q000502:physiology*; D012038:Regeneration; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
C486197:Ccnd2 protein, rat; D056741:Cyclin D; D056742:Cyclin D2; D016213:Cyclins; D007328:Insulin; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8