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Blood, 15 December 2006, Vol. 108, No. 13, pp. 3959-3960.
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HEMOSTASIS
Comment on Pula et al, page 4035
Uncovering the dark side of PKC
Ulhas P. Naik
UNIVERSITY OF DELAWARE
In this issue of Blood, Pula and colleagues provide a novel mechanism for the negative regulatory role of platelet protein kinase C  (PKC) that is independent of inside-out signaling, granular secretion, or early steps of GPVI signaling.
The initial step of agonist-induced platelet activation is platelet shape change, which is associated with intracellular calcium rise, phosphorylation of pleckstrin by PKC, and myosin light chain (MLC) by MLC kinase, followed by cytoskeletal rearrangement. Human platelets predominantly express 4 of the 12 known PKC isoforms.1 Although PKC ,  , and  have been shown to positively regulate platelet activation, PKC is unique in that it plays a positive as well as a negative regulatory role.2,3
In this issue, Pula and colleagues provide convincing evidence regarding the negative role of PKC in platelet aggregation and reveal a novel mechanism for regulation of actin and filopodia. Filopodia are membranous protrusions formed and supported by bundles of actin filaments and are followed by lamellipodia formation leading to platelet spreading.4 Vasodilator-stimulated phosphoprotein (VASP) regulates actin polymerization and hence filopodia formation primarily through its anticapping activity. VASP is a major substrate of protein kinase A, protein kinase G, and PKC, which phosphorylate it on Ser157, Ser239, and Thr278. Phosphorylation of VASP on Ser157 is required for its anticapping activity.5
In previous studies using pharmacological agents, it was suggested that PKC negatively regulates collagen-induced dense granule secretion.3 Using PKC knockout mice, Pula and colleagues show that negative regulation of platelet aggregation by PKC is independent of inside-out signaling, dense granule secretion, and early GPVI signaling. They also provide evidence that PKC physically interacts with VASP and inhibits VASP phosphorylation on Ser157 by classical PKC (cPKC) isoforms, thus suppressing actin polymerization and filopodia formation. The fact that cPKCs' ability to phosphorylate other platelet proteins is unaffected by the inhibition or absence of PKC suggests that PKC does not directly inhibit the activity of these enzymes. This workundoubtedly provides provocative new ideas and will inspire new studies investigating how association of VASP and PKC inhibit phosphorylation of VASP on Ser157. The evidence presented strongly suggests that the PKC activity is necessary for the observed negative regulation.
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PKC negatively regulates filopodia formation in human platelets. See the complete figure in the article beginning on page 4035.
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Future studies aimed at (1) the stoichiometry of PKC interaction with VASP, (2) how PKC activity is involved in inhibiting filopodia formation, (3) whether PKC activation is required for its interaction with VASP, (4) whether steric hindrance or conformational change resulting from PKC binding is responsible for decreased VASP phosphorylation on Ser157, and (5) whether PKC is constitutively associated with VASP in resting platelets or whether it becomes associated upon stimulation of platelets will be very interesting. Thus, this work, using a genetic approach, provides an intriguing avenue for further studies that might aid in design and development of novel therapeutic agents for the treatment of thrombotic disorders.
The author declares no competing financial interest. 
References
- Jaken S. Protein kinase C isozymes and substrates. Curr Opin Cell Biol. 1996;8: 168-173.[CrossRef][Medline]
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- Moussazadeh M, Haimovich B. Protein kinase C-delta activation and tyrosine phosphorylation in platelets. FEBS Lett. 1998;438: 225-230.[CrossRef][Medline]
[Order article via Infotrieve]
- Murugappan S, Tuluc F, Dorsam RT, Shankar H, Kunapuli SP. Differential role of protein kinase C delta isoform in agonist-induced dense granule secretion in human platelets. J Biol Chem. 2004;279: 2360-2367.[Abstract/Free Full Text]
- Naik UP, Naik MU. Association of CIB with GPIIb/IIIa during outside-in signaling is required for platelet spreading on fibrinogen. Blood. 2003;102: 1355-1362.[Abstract/Free Full Text]
- Barzik M, Kotova TI, Higgs HN, et al. Ena/VASP proteins enhance actin polymerization in the presence of barbed end capping proteins. J Biol Chem. 2005;280: 28653-28662.[Abstract/Free Full Text]
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Related Article in Blood Online:
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PKC regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation
- Giordano Pula, Kai Schuh, Keiko Nakayama, Keiichi I. Nakayama, Ulrich Walter, and Alastair W. Poole
Blood 2006 108: 4035-4044.
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