A novel tyrosine phosphorylation site in protein kinase D contributes to oxidative stress-mediated activation

Protein kinase D1 (PKD1) is a mediator of oxidative stress signaling where it regulates cellular detoxification and survival. Critical for the regulation of PKD1 activity in response to oxidative stress are Src- and Abl-mediated tyrosine phosphorylations that eventually lead to protein kinase Cδ(PKCδ)-mediated activation of PKD1. Here we identify Tyr ⁹⁵ in PKD1 as a previously undescribed phosphorylation site that is regulated by oxidative stress. Our data suggest that PKD1 phosphorylation at Tyr⁹⁵ generates a binding motif for PKCδ, and that oxidative stress-mediated PKCδ/PKD interaction results in PKD1 activation loop phosphorylation and activation. We further analyzed all PKD isoforms for this mechanism and show that PKD enzymes PKD1 and PKD2 are targets for PKCδ in response to oxidative stress, and that PKD3 is not a target because it lacks the relevant tyrosine residue that generates a PKCδ interaction motif.