A phosphoproteomic approach reveals that PKD3 controls PKA-mediated glucose and tyrosine metabolism

Abstract

Members of the protein kinase D (PKD) family (PKD1, 2, and 3) integrate hormonal and nutritional inputs to regulate complex cellular metabolism. Despite the fact that a number of functions have been annotated to particular PKDs, their molecular targets are relatively poorly explored. PKD3 promotes insulin sensitivity and suppresses lipogenesis in the liver of animals fed a high-fat diet. However, its substrates are largely unknown. Here we applied proteomic approaches to determine PKD3 targets. We identified more than 300 putative targets of PKD3. Furthermore, biochemical analysis revealed that PKD3 regulates cAMP-dependent PKA activity, a master regulator of the hepatic response to glucagon and fasting. PKA regulates glucose, lipid, and amino acid metabolism in the liver, by targeting key enzymes in the respective processes. Among them the PKA targets phenylalanine hydroxylase (PAH) catalyzes the conversion of phenylalanine to tyrosine. Consistently, we showed that PKD3 is activated by glucagon and promotes glucose and tyrosine levels in hepatocytes. Therefore, our data indicate that PKD3 might play a role in the hepatic response to glucagon.

Platelet‐derived lipids promote insulin secretion of pancreatic β cells

“…As indicated by an antibody that recognizes phosphorylation of s916 on PKD1 and s876 on PKD2 as well as an antibody that recognizes s744 and 748 in all PKD members (Trujillo‐Viera et al , 2021 ), the activity of PKD was increased in response to the stimulation with hPS (Fig 7G ). Consistently, using an antibody that recognizes phosphorylation motive in PKD's substrate proteins (Loza‐Valdes et al , 2021 ), we confirmed the increased activity of these kinases in β cells in response to hPS stimulation (Fig 7G ). Finally, inhibition of PKDs with the specific inhibitor (CRT 0066101) in β cells abrogated hPS‐induced insulin secretion (Fig 7H ).…”

Aggravated hepatic fibrosis induced by phenylalanine and tyrosine was ameliorated by chitooligosaccharides supplementation

“… 41 Most Phe is oxidized to Tyr, which is metabolized by rate-limiting hepatic enzymes, including TAT and TYR, and then further used to synthesize substances involved in lipid and carbohydrate metabolism. 41 , 42 COS indeed promoted the metabolism of Phe and Tyr, which might be attributed to the increase in the expression level of TAT, TYR, and PAH in this study. Previous studies showed that COS improved liver injury through antioxidant effect, regulating the polarization of M1 and M2 macrophages, etc., 21 , 43 while the effects of COS in anti-hepatic fibrosis might be related to the decrease of Phe and Tyr levels in this study.…”

Mechanism of Paeoniflorin on ANIT-Induced Cholestatic Liver Injury Using Integrated Metabolomics and Network Pharmacology

“…Amino acid metabolism exists in every cell of the organism, and the occurrence of disease and health status are directly or indirectly related to amino acids. Studies have shown that severe damage to liver cells can cause amino acid metabolism disorder (Loza-Valdes et al, 2021). By studying the significantly changed amino acids, we can further clarify the mechanism of PF in the treatment of cholestasis liver injury.…”