Mechanisms of Regulation of Protein Kinase C and Its Tumor Suppressor Function in Cancer
- Author(s): Antal, Corina Elena
- et al.
The serine/threonine protein kinase C (PKC) family has been extensively studied over the last 35 years, yet fundamental questions regarding the regulation of its signaling and its dysregulation in disease remain unanswered. PKC is involved in a multitude of cellular processes and precise control of the amplitude of PKC signaling is essential for maintaining cellular homeostasis. This thesis expands on the knowledge of PKC at the molecular level by unveiling how intramolecular conformational changes tune the affinity of PKC for its ligands, and at the pathophysiological level by overturning a 30-year-old scientific dogma on the role of PKC in cancer. First, mechanistic studies reveal that processing phosphorylations promote intramolecular interactions that clamp PKC in a closed conformation to prevent signaling in the absence of agonists, but allow efficient activation in response to small changes in agonist levels. These studies offer novel means of therapeutically targeting PKC with molecules or peptides that can either disrupt these interactions to activate PKC or maintain them closed to inhibit PKC activity. Second, analysis of PKC gene family mutations in human cancers reveals that they are loss-of-function, and that this loss -of-function confers a growth advantage, both in vitro and in vivo. These data suggest that therapies should focus on restoring, not inhibiting, PKC activity in the treatment of cancer. Taken together, this thesis identifies novel strategies to modulate PKC activity in therapies and, most importantly, establishes that PKC is a tumor suppressor