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Blood, 1 October 2009, Vol. 114, No. 14, pp. 2856-2857. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Naik, U. P. PubMed PubMed Citation Articles by Naik, U. P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLATELETS & THROMBOPOIESIS Comment on Chari et al, page 3056 Lyn and PKC order SHIP1 embargo Ulhas P. Naik UNIVERSITY OF DELAWARE In this issue of Blood, Chari and colleagues provide a novel mechanism for the unique negative regulatory role of PKC in platelet dense granule release downstream of collagen signaling. Upon vascular injury, platelets adhere to collagen and release dense granule content to recruit more circulating platelets to an injured site. This process is initiated by signaling through glycoprotein VI (GPVI), a major platelet collagen receptor, leading to intracellular calcium mobilization and the activation of protein kinase C (PKC) isoforms. Of the 7 PKC isoforms expressed in platelets, PKC differentially regulates dense granule release in platelets; it positively regulates dense granule release by thrombin and negatively regulates it by collagen.1 View larger version (61K): [in this window] [in a new window]   Schematic representation of the signaling events that are initiated on binding of collagen, convulxin, or collagen-related peptide (CRP) to platelet GPVI receptor complex leading to dense granule release.   Chari et al provide convincing evidence regarding the negative regulation of dense granule release downstream of GPVI signaling and reveal a new association of PKC with Lyn and SHIP1.1 Lyn is an important member of the Src tyrosine kinase family that functions downstream of GPVI, whereas SHIP1 is a lipid phosphatase that regulates PIP3 levels in platelets.2 SHIP1 associates with members of the Src family of protein kinases and is phosphorylated on Y1020, leading to its activation.3 Activation of GPVI results in activation of Syk, which activates LAT, leading to the generation of diacylglycerol (DAG) and IP3 through activation of PLC. IP3 induces release of Ca2+ from intracellular stores whereas DAG activates several isoforms of PKC in a Ca2+-dependent manner, leading to dense granule release.4 Using both pharmacologic agents and PKC-null murine platelets, it has been previously shown that PKC, which is also activated by DAG, exerts a negative effect on dense granule release induced by collagen.5–7 Here, Chari et al show that PKC selectively associates with tyrosine-phosphorylated SHIP1 downstream of GPVI, but not with thrombin receptors.1 This association is absent in Lyn knockout murine platelets, suggesting a role for Lyn-mediated tyrosine phosphorylation of SHIP1. Furthermore, SHIP1 tyrosine phosphorylation is diminished in PKC-null mice, suggesting a role for PKC in bringing Lyn and SHIP1 together. Most interestingly, when this ternary interaction among Lyn, SHIP1, and PKC fails due to the absence of any one of the members, collagen-induced dense granule release is potentiated. Thus, the tight association through phosphorylation events among Lyn, SHIP1, and PKC puts an embargo on dense granule release induced through GPVI signaling (outlined in the figure). As SHIP1 is known to reduce levels of PIP3, an important enhancer of platelet functions, it is possible that the negative regulation is achieved by hydrolysis of PIP3 by SHIP1 that is associated with and possibly regulated by PKC. Future studies should answer some of these intriguing questions: Does PKC, a serine threonine kinase, phosphorylate the serine residues of SHIP1? Does the phosphorylation of serine residues of SHIP1 affect its catalytic activity? Does Lyn directly phosphorylate SHIP1 or is some other tyrosine kinase involved in this process? Does PKC serve as an adapter protein to bring Lyn and SHIP1 together? What is the mechanism of the association of PKC with SHIP1? Why does SHIP1 only associate with PKC downstream of GPVI? Are there other targets of PKC that regulate dense granule release? Thus, using a combination of biochemical, pharmacologic, and genetic approaches, Chari et al provide an intriguing avenue for further studies that will enhance our knowledge about platelet dense granule release. These insights may also aid in design and development of novel therapeutic agents for the treatment of thrombotic disorders. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Chari R, Kim S, Murugappan S, Sanjay A, Daniel JL, Kunapuli SP. Lyn, PKC-delta, SHIP-1 interactions regulate GPVI-mediated platelet-dense granule secretion. Blood. 2009;114(14):3056–3063.[Abstract/Free Full Text] Giuriato S, Pesesse X, Bodin S, et al. SH2-containing inositol 5-phosphatases 1 and 2 in blood platelets: their interactions and roles in the control of phosphatidylinositol 3, 4, 5-trisphosphate levels. Biochem J. 2003;376(Pt 1):199–207.[CrossRef][Medline] [Order article via Infotrieve] Crosby D, Poole AW. Physical and functional interaction between protein kinase C delta and Fyn tyrosine kinase in human platelets. J Biol Chem. 2003;278(27):24533–24541.[Abstract/Free Full Text] Konopatskaya O, Gilio K, Harper MT, et al. PKCalpha regulates platelet granule secretion and thrombus formation in mice. J Clin Invest. 2009;119(2):399–407.[Medline] [Order article via Infotrieve] Chari R, Getz T, Nagy B Jr, et al. Protein kinase C differentially regulates platelet functional responses. Arterioscler Thromb Vasc Biol. 2009;29(5):699–705.[Abstract/Free Full Text] Murugappan S, Chari R, Palli VM, Jin J, Kunapuli SP. Differential regulation of threonine and tyrosine phosphorylations on protein kinase Cdelta by G-protein-mediated pathways in platelets. Biochem J. 2009;417(1):113–120.[CrossRef][Medline] [Order article via Infotrieve] Pula G, Schuh K, Nakayama K, Nakayama KI, Walter U, Poole AW. PKCdelta regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation. Blood. 2006;108(13):4035–4044.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Lyn, PKC-, SHIP-1 interactions regulate GPVI-mediated platelet-dense granule secretion Ramya Chari, Soochong Kim, Swaminathan Murugappan, Archana Sanjay, James L. Daniel, and Satya P. Kunapuli Blood 2009 114: 3056-3063. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Naik, U. P. PubMed PubMed Citation Articles by Naik, U. P. 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