(a) Classical activation of PKD downstream of phospholipase C activity. (1) PKD1 is in an inactive resting conformation: the C1 and PH domains autoinhibit PKD activity. (2) PKD1 is recruited to DAG-containing microenvironments at the plasma membrane, which alleviates the autoinhibition exerted by the C1 domains. In this conformation, PKD has increased activity towards peptide substrates, but not towards proteins, indicative of an “unstable” open or “half-open” conformation. At this point, PKD can also exert autocatalytic activity towards Ser-910. (3) The abovementioned conformational changes and Ser-910 phosphorylation structure the kinase core for subsequent Ser-738 and Ser-742 phosphorylation by upstream PKCs. (4) Activation loop Ser phosphorylation stabilizes the PH-CAT module in an “open” conformation allowing for full PKD activity. (5) PKD1 is released from the membrane and translocates to several compartments to exert its functions. (b) Activation of PKD1 in oxidative stress conditions. (1) PKD1 is in a resting state, confer (a). (2) Activation is initiated by phosphorylation of Tyr-463 in the PH domain, which allows the recruitment of PKD to DAG generated by phospholipase D (PLD) activity at the outer mitochondrial membrane. (3) A subsequent conformational change allows for N-terminal phosphorylation at Tyr-95. (4) PKCδ docks to PKD1 via pTyr-95 and phosphorylates PKD1 at the activation loop Ser-738/742 residues. (5) PKD1 reaches full activity and initiates downstream signaling. (c) Activation of PKD2 in oxidative stress conditions. (1) PKD2 is in a resting state, confer (a). (2) PKD2 is recruited to DAG generated by phospholipase D (PLD) and phosphatidic acid phosphatase (PAP) activity at the outer mitochondrial membrane via its C1 domains, where it colocalizes and interacts with PKCδ without the need for Tyr-95 phosphorylation. PKCδ phosphorylates PKD2 at the activation loop Ser-706/710 residues. (3) PKD2 is phosphorylated at Tyr residues, including Tyr-87, Tyr-438, and Tyr-717, with no determined hierarchy. (4) An active and Tyr-phosphorylated PKD2 species is released from the membrane to exert its functions. PIP2: phosphatidylinositol 4,5-bisphosphate; IP3: inositol 1,4,5-trisphosphate; PC: phosphatidylcholine; PA: phosphatidic acid; DAG: diacylglycerol. Tyr phosphorylation sites are indicated with yellow-coloured circles, and Ser phosphorylation sites are indicated with red-coloured circles.