Diacylglycerol Signaling

7 Regulation and Function of Protein Kinase D Signaling
provided the first evidence indicating the operation of a PKC/PKD signaling cascade
in response to receptor-activated pathways.
Subsequently, the functioning of PKC-dependent PKD activation has been
extended and further explored in many normal cell types, including fibroblasts
(Matthews et al. 1997; Chiu and Rozengurt 2001a; Zhukova et al. 2001a), intestinal
and kidney epithelial cells (Rey et al. 2001a; Chiu and Rozengurt 2001b; Chiu et al.
2002; Rey et al. 2004), smooth muscle cells (Abedi et al. 1998), cardiomyocytes
(Haworth et al. 2000; Haworth et al. 2004), neuronal cells (Iglesias et al. 2000a;
Wang et al. 2004; Song et al. 2007; Poole et al. 2008), human mesenchymal stem
cells (Celil and Campbell 2005), osteoblasts (Lemonnier et al. 2004), pancreatic
exocrine (Yuan et al. 2008; Berna et al. 2007) and endocrine b cells (Liuwantara
et al. 2006), B and T lymphocytes (Sidorenko et al. 1996; Matthews et al. 2000a;
Matthews et al. 1999a), mast cells (Matthews et al. 1999b), bone marrow-derived
mast cells (Murphy et al. 2007), macrophages (Park et al. 2008) and platelets
(Stafford et al. 2003), as well as in a variety of cancer cells, including cells derived
from small cell lung carcinoma, ductal pancreatic adenocarcinoma and breast and
prostate cancer (Paolucci and Rozengurt 1999; Guha et al. 2002; Mihailovic et al.
2004; Qiang et al. 2004; Jaggi et al. 2005). These studies revealed PKD activation
in response to regulatory peptides, including angiotensin, bombesin/gastrin-releasing
peptide, cholecystokinin, neurotensin, vasopressin (Zugaza et al. 1997; Chiu and
Rozengurt 2001a; Zhukova et al. 2001b; Chiu and Rozengurt 2001b; Chiu et al. 2002;
Guha et al. 2002; Zhukova et al. 2001a; Sinnett-Smith et al. 2004), the potent bioactive
lipid mediator LPA (Chiu and Rozengurt 2001b; Paolucci et al. 2000; Yuan et al.
2003) and thrombin (Stafford et al. 2003) that act through G q , G 12 , G i and Rho (Chiu
and Rozengurt 2001b; Paolucci et al. 2000; Yuan et al. 2003; Yuan et al. 2000; Yuan
et al. 2001), as well as polypeptide growth factors, such as PDGF (Zugaza et al. 1997;
Abedi et al. 1998; Van Lint et al. 1998), VEGF (Wong and Jin 2005), BMP-2 (Celil
and Campbell 2005) and IGF (Celil and Campbell 2005; Qiang et al. 2004), crosslinking
of B-cell receptor and T-cell receptor in B and T lymphocytes, respectively
(Sidorenko et al. 1996; Matthews et al. 2000a, b; Matthews et al. 1999a), agonist
stimulation of TLR2 (Murphy et al. 2007) and TLR9 (Park et al. 2008), aldosterone
(McEneaney et al. 2007) and oxidative stress (Waldron and Rozengurt 2000; Waldron
et al. 2004; Storz and Toker 2003; Zhang et al. 2005a).
Collectively, these studies demonstrated rapid PKC-dependent PKD activation
in a broad range of biological systems but did not exclude the possibility of PKD
activation through PKC-independent mechanism(s).
7.2.2 PKCs Directly Phosphorylate PKD at the Activation Loop
For many protein kinases, catalytic activity is dependent on the phosphorylation of
activating residues located in a region spanning the highly conserved sequences
DFG (in kinase subdomain VII) and APE (in kinase subdomain VIII) of the kinase
catalytic domain termed the “activation loop” or “activation segment.” At least two
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