Table 2.
Representative PKC substrates and the effect of their phosphorylation
| Substrate | Effect of Substrate Phosphorylation | Reference |
|---|---|---|
| Histones | ||
| H3T45 | DNA fragmentation, apoptosis | (Hurd et al., 2009) |
| H3T6 | Prevents LSD1 from demethylating H3K4 during androgen receptor-dependent gene activation. Promotes cell proliferation | (Metzger et al., 2010) |
| Membrane-bound proteins | ||
| MARCKS (myristoylated, alanine-rich C kinase substrate) | MARCKS is bound to F-actin. Functions as cross-bridge between cytoskeletal actin and plasma membrane | (Hartwig et al., 1992) |
| The inhibitory GTP-binding protein Gi | Facilitates the dissociation of the αi subunit from adenylyl cyclase and thereby relieves it from inhibition. | (Kanashiro and Khalil, 1998) |
| Ion Channels | ||
| BKCa channels | Inhibition, leading to membrane depolarization, activation of L-type voltage-gated Ca2+ channels, and increased [Ca2+]i and vascular tone, e.g. in pulmonary artery and porcine coronary artery. | (Minami et al., 1993; Lange et al., 1997; Taguchi et al., 2000; Barman et al., 2004; Crozatier, 2006; Ledoux et al., 2006; Zhu et al., 2013) |
| Voltage-gated K+ channel | Inhibition. Increases vascular tone | (Cogolludo et al., 2003; Novokhatska et al., 2013; Zhu et al., 2013; Brueggemann et al., 2014) |
| KATP channels | Inhibition. Alters the channel properties by modifying kinetics and/or the number of channels at the cell membrane, e.g. in mesenteric artery | (Levitan, 1994; Bonev and Nelson, 1996; Light, 1996; Zhu et al., 2013) |
| Store-operated Ca2+ channel | HEK293 cells. Inhibition. | (Shi et al., 2004) |
| Ion Pumps & Exchangers | ||
| Ca2+-ATPase activation | Activation. Promotes Ca2+ extrusion. Explains transient nature of agonist-induced increase in VSM [Ca2+]i. | (Salamanca and Khalil, 2005) |
| α1 subunit of Na+/K+-ATPase | Inhibition. Alters membrane potential and intracellular concentrations of Na+ and K+ | (Bertorello et al., 1991) |
| Na+/H+ antiport exchanger | Activation. Increases cytoplasmic pH, which increases contraction | (Aviv, 1994; Austin and Wray, 2000; Wray and Smith, 2004) |
| Cytoskeletal & Regulatory Proteins | ||
| Vinculin | Controls cell shape and adhesion | (Perez-Moreno et al., 1998) |
| Vimentin | Recycles β1-integrins to plasma membrane | (Ivaska et al., 2005) |
| CPI-17 | Enhances myofilament force sensitivity to Ca2+. Inhibits MLC phosphatase, increases MLC phosphorylation and enhances VSM contraction, e.g. in rabbit femoral artery | (Woodsome et al., 2001) |
| Calponin | Allows actin-myosin interaction and enhances VSM contraction | (Parker et al., 1994) |
| Raf | Initiates a cascade involving MAPK kinase (MEK) and MAPK, and phosphorylation of the actin-binding protein caldesmon (CaD) which reverses its inhibition of MgATPase activity and thus increases actin–myosin interaction and VSM contraction | (Khalil et al., 1995; Kim et al., 2008) |
| 20-kDa MLC and MLCK | Counteracts Ca2+-induced actin–myosin interaction and force development, e.g. in In rabbit mesenteric artery | (Inagaki et al., 1987) |
| Ribosomal Protein Kinases | ||
| S6KβII | Nucleocytoplasmic shuttling of S6KβII. Regulates protein synthesis and the G1/S transition in the cell cycle | (Valovka et al., 2003) |
| Other | ||
| Arginine-rich protein substrates | Neutralizes the acidic patch in the substrate binding site. Displaces PKC pseudosubstrate from the kinase core | (House and Kemp, 1987; Newton, 1995) |