Inhibition of Cdk5 Promotes β-Cell Differentiation From Ductal Progenitors

Abstract

Inhibition of notch signaling is known to induce differentiation of endocrine cells in zebrafish and mouse. After performing an unbiased in vivo screen of ∼2,200 small molecules in zebrafish, we identified an inhibitor of Cdk5 (roscovitine), which potentiated the formation of β-cells along the intrapancreatic duct during concurrent inhibition of notch signaling. We confirmed and characterized the effect with a more selective Cdk5 inhibitor, (R)-DRF053, which specifically increased the number of duct-derived β-cells without affecting their proliferation. By duct-specific overexpression of the endogenous Cdk5 inhibitors Cdk5rap1 or Cdkal1 (which previously have been linked to diabetes in genome-wide association studies), as well as deleting , we validated the role of chemical Cdk5 inhibition in β-cell differentiation by genetic means. Moreover, the mutant zebrafish displayed an increased number of β-cells independently of inhibition of notch signaling, in both the basal state and during β-cell regeneration. Importantly, the effect of Cdk5 inhibition to promote β-cell formation was conserved in mouse embryonic pancreatic explants, adult mice with pancreatic ductal ligation injury, and human induced pluripotent stem (iPS) cells. Thus, we have revealed a previously unknown role of Cdk5 as an endogenous suppressor of β-cell differentiation and thereby further highlighted its importance in diabetes.

[Corrigendum]Phosphorylation of cortactin by cyclin-dependent kinase�5 modulates actin bundling by the dynamin 1-cortactin ring-like complex and formation of filopodia and lamellipodia in NG108-15 glioma-derived cells

“…CDK5 has been investigated in terminally differentiated cells, such as neurons and neuroendocrine cells (10,11). In synapses, phosphorylation of dynamin 1 by CDK5 is crucial for regulation of endocytosis, and dynamin 1 is phosphorylated at S774 and S778 in rats and sheep (16) as well as T780 in bovine (17).…”

“…The role of CDK5 has been mostly studied in terminally differentiated cells, including neurons and neuroendocrine cells. CDK5 contributes to neurite outgrowth, neuronal migration, and neuronal and β cell differentiation (10,11). In addition, it has recently been demonstrated that CDK5 is highly expressed in several cancer cell lines and tissues, suggesting this kinase is functionally associated with tumorigenesis and/or malignancy (12).…”

Neurogenin3 phosphorylation controls reprogramming efficiency of pancreatic ductal organoids into endocrine cells

“…This indicates that growth factors suppress insulin expression by additional mechanisms as well as promoting phosphorylation of Ngn3 protein and thereby restricting its ability to drive the differentiation programme. Thus, the incorporation of phosphomutant Ngn3 and/or cdk inhibitors alongside further manipulation of the growth factor environment could be explored to further increase efficiency of β-cell generation in other in vitro reprogramming protocols 28 , 31 , 42 .…”

Association between single nucleotide polymorphisms in CDKAL1 and HHEX and type 2 diabetes in Chinese Population

“…Cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1 (CDKAL1) gene encodes cyclin-dependent kinase 5 regulatory subunit-associated protein 1 (CDK5RAP1)-like 1,which is homologous to the CDK5RAP1, inhibitor of the CDK5 kinase through the inhibition of the CDK5 activator p35 [5,6]. CDK5 is a serine/threonine protein kinase which is involved in the glucose-dependent regulation of the insulin secretion, therefore, it plays a tolerant role in the pathophysiology of β-cell dysfunction and predisposition to T2DM [7,8].…”