Protein kinase C regulates ErbB3 turnover.

ErbB3, which belongs to the epidermal growth factor receptor (EGFR) or ErbB family of receptor tyrosine kinases, is involved in progression of several human cancers and a tight regulation of its expression is crucial. An important mechanism for regulation of ErbB proteins is endocytosis and we recently showed that ErbB3, contrary to other ErbB proteins, like EGFR and ErbB2, is constitutively internalized and degraded. Several studies show that protein kinase C (PKC) can regulate the activation, localization and stability of EGFR and ErbB2. Activation of PKC causes their down-regulation from the plasma membrane, but instead of being degraded the receptors accumulate in an endosomal recycling compartment. Since little is known about possible connections between ErbB3 and PKC, we have in the present study investigated effects PKC activity has on ErbB3 stability and intracellular trafficking. While PKC inhibition tends to increase ErbB3 degradation, activation of PKC causes ErbB3 stabilization. The stabilization was not due to inhibited internalization, on the contrary we find that expression of ErbB3 at the plasma membrane is reduced upon PMA-induced PKC activation. However, while endocytosed ErbB3 under normal conditions and upon PKC inhibition is found in early endosomal antigen 1 (EEA1) positive early endosomes and lysosomal-associated membrane protein 1 (LAMP1) positive late endosomes/lysosomes, indicating that it follows the classic degradative pathway, ErbB3 localizes to EEA1 and LAMP1 negative compartments upon PMA-induced activation of PKC. Altogether this shows that PKC regulates the stability of ErbB3, and knockdown experiments show that PKCδ is essential in this process. A likely explanation is that PKC regulates endosomal sorting of ErbB3 and that activated PKC sorts ErbB3 away from the degradative pathway.