TY - JOUR T1 - Decoding the cardiac actions of protein kinase D isoforms JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/molpharm.121.000341 SP - MOLPHARM-AR-2021-000341 AU - Susan F. Steinberg Y1 - 2021/01/01 UR - http://molpharm.aspetjournals.org/content/early/2021/09/16/molpharm.121.000341.abstract N2 - Protein kinase D (PKD) consists of a family of three structurally related enzymes that play key roles in a wide range of biological functions that contribute to the evolution of cardiac hypertrophy and heart failure. PKD1 (the founding member of this enzyme family) has been implicated in the phosphorylation of substrates that regulate cardiac hypertrophy, contraction, and susceptibility to ischemia/reperfusion injury and de novo PRKD1 mutations have been identified in patients with syndromic congenital heart disease. However, cardiomyocytes co-express all three PKDs; while stimulus-specific activation patterns for PKD1, PKD2, and PKD3 have been identified in cardiomyocytes, progress toward identifying PKD isoform-specific functions in the heart have been hampered by significant gaps in our understanding of the molecular mechanisms that regulate PKD activity. This review incorporates recent conceptual breakthroughs in our understanding of various alternative mechanisms for PKD activation, with an emphasis on the recent evidence that PKDs activate certain effector responses as dimers, to consider the role of PKD isoforms in signaling pathways that drive cardiac hypertrophy and ischemia/reperfusion injury. The focus is on whether recently identified activation mechanisms that enhance the signaling repertoire of PKD family enzymes provide novel therapeutic strategies to target PKD enzymes and prevent or slow the evolution of cardiac injury and pathological cardiac remodeling. Significance Statement PKD isoforms regulate a large number of fundamental biological processes, but our understanding of the biological actions of individual PKDs (based upon studies using adenoviral overexpression or gene silencing methods) remains incomplete. This review focuses on dimerization, a recently identified mechanism for PKD activation, and the notion that this mechanism provides a strategy to develop novel PKD-targeted pharmaceuticals that restrict proliferation, invasion, or angiogenesis in cancer and prevent or slow the evolution of cardiac injury and pathological cardiac remodeling. ER -