PT  - JOURNAL ARTICLE
AU  - Alexander E. Mayer
AU  - Angel Loza-Valdes
AU  - Werner Schmitz
AU  - Jonathan Trujillo Viera
AU  - Michael Leitges
AU  - Andreas Schlosser
AU  - Grzegorz Sumara
TI  - A phosphoproteomic approach reveals that PKD3 controls phenylalanine and tyrosine metabolism
AID  - 10.1101/2020.07.20.211474
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.20.211474
4099  - http://biorxiv.org/content/early/2020/07/22/2020.07.20.211474.short
4100  - http://biorxiv.org/content/early/2020/07/22/2020.07.20.211474.full
AB  - 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. However, its substrates are largely unknown. Here we applied proteomic approaches to determine PKD3 targets. We identified over three-hundred putative targets of PKD3. Among them phenylalanine hydroxylase (PAH). PAH catalyses the conversion of phenylalanine to tyrosine and its activity is regulated by, phenylalanine concentration and glucagon-induced signaling. Consistently, we showed that PKD3 is activated by glucagon and promotes tyrosine levels in primary hepatocytes and liver of mice.Taken together, our comprehensive proteomic approach established that PKD3 determine the rate of phenylalanine to tyrosine conversion in the liver. Therefore, our data indicate that PKD3 might play a role in development of diseases related to the defective tyrosine and phenylalanine metabolism.