ABSTRACT
Protein Kinase C (PKC)-Dependent ADAM17-Regulated Ectodomain Shedding Induction of PKC by phorbol esters, specifi cally by PMA or 12-O-tetradecanoylphorbol-13-acetate (TPA), is a hallmark feature of ectodomain shedding. Diff erent proteins are shed in response to PKC activation –i.e. EGF, TGFa, heparin-binding EGF (HB-EGF), interleukins (ILs), IL-6 receptor a (IL6Ra), L-selectin, amyloid precursor protein, neuregulin and VEGFR-1 (Th abard et al. 2001; Wheeler et al. 2003; Rahimi et al. 2009; Hayashida et al. 2010), and using specifi c inhibitors or cells lacking expression of ADAM17 (ADAM17-/–), it has been demonstrated that PKC-mediated ectodomain cleavage occurs in many instances via the activation of ADAM17 (Montero et al. 2002; Sahin et al. 2004; Rahimi et al. 2009; Kveiborg et al. 2011). As is the case for other MAPKs, diff erent PKC isoforms are known to regulate shedding in a cell type specifi c manner. For example, activation of the PKCd and h isoforms controls the shedding of IL6Ra in myeloma cells, while PKCd regulates the basal and induced shedding of HB-EGF in fi brosarcoma cells (Kveiborg et al. 2011) and neuregulin shedding in Chinese hamster ovary (CHO) cells, PC12 and primary neuronal cultures (Esper and Loeb 2009). Moreover, shedding of the same substrate can be regulated by diff erent PKC isoforms depending on the stimulus (Herrlich et al. 2008; Dang et al. 2011). Even the same stimulus can activate diff erent PKC isoforms as it is described for HB-EGF shedding aft er PMA stimulation in fi brosarcoma cells which results in PCKa and PKCd activation (Kveiborg et al. 2011; Dang et al. 2011). In this case, it has been suggested that activation of both PKC isoforms acts in parallel to promote regulated and basal shedding of HB-EGF.
