title: Role of the SIK2-p35-PJA2 complex in pancreatic β-cell functional compensation.
abstract: Energy sensing by the AMP-activated protein kinase (AMPK) is of fundamental importance in cell biology. In the pancreatic β-cell, AMPK is a central regulator of insulin secretion. The capacity of the β-cell to increase insulin output is a critical compensatory mechanism in prediabetes, yet its molecular underpinnings are unclear. Here we delineate a complex consisting of the AMPK-related kinase SIK2, the CDK5 activator CDK5R1 (also known as p35) and the E3 ligase PJA2 essential for β-cell functional compensation. Following glucose stimulation, SIK2 phosphorylates p35 at Ser 91, to trigger its ubiquitylation by PJA2 and promote insulin secretion. Furthermore, SIK2 accumulates in β-cells in models of metabolic syndrome to permit compensatory secretion; in contrast, β-cell knockout of SIK2 leads to accumulation of p35 and impaired secretion. This work demonstrates that the SIK2-p35-PJA2 complex is essential for glucose homeostasis and provides a link between p35-CDK5 and the AMPK family in excitable cells.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Sakamaki
authors.forename: Accalia
authors.initials: A
authors.lastname: Fu
authors.forename: Courtney
authors.initials: C
authors.lastname: Reeks
authors.forename: Stephen
authors.initials: S
authors.lastname: Baird
authors.forename: Chantal
authors.initials: C
authors.lastname: Depatie
authors.forename: Mufida
authors.initials: M
authors.lastname: Al Azzabi
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.forename: Siu-Pok
authors.initials: SP
authors.lastname: Yee
authors.forename: Robert A
authors.initials: RA
authors.lastname: Screaton
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D005260:Female; D005947:Glucose / Q000502:physiology; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C492236:Cdk5r1 protein, mouse; D007328:Insulin; C588034:PJA2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D010770:Phosphotransferases; C474808:salt-inducible kinase-2, mouse; D017346:Protein Serine-Threonine Kinases; D005947:Glucose