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PKD inhibitor treatment results in increased PKD activation loop phosphorylation (1055.1)

Protein kinase D (PKD) transduces an abundance of signals downstream of diacylglycerol (DAG) production and plays a role in many cellular functions, including regulation of Golgi sorting, apoptosis, cell growth, and cell survival. PKD1, originally described as a protein kinase C (PKC) family member and named PKCμ, is now known to be a member of a distinct family of kinases that includes, PKD1, PKD2, and PKD3. The PKD family is related to members of the calcium‐calmodulin kinase (CAMK) superfamily of kinases rather than the PKCs, which belong to the AGC kinase group. PKD activity is acutely regulated via binding to membrane DAG via its C1 domains. Subsequent to DAG binding, PKD is activated via phosphorylation by the upstream kinases, the novel PKCs, at the activation loop followed by autophosphorylation. Thus, this phosphorylated species is often used as a measure of kinase activity. Here we describe that PKD inhibitors promote activation loop phosphorylation downstream of G protein‐coupled receptors. This is reminiscent of similar observations for PKC and Akt, wherein active site inhibitors trap phosphates on the kinase; a phenomenon we have attributed to stabilization of a phosphatase‐resistant conformation of the kinase domain. For PKD, this effect occurred in the presence of active site inhibitors as well as in the presence of non‐competitive inhibitors, a distinction from PKC. These findings underscore the importance of using caution when interpreting kinase activity from kinase phosphorylation status in the presence of small molecule inhibitors.