Protein Kinase C δ Deficiency Enhances Megakaryopoiesis and Recovery from Thrombocytopenia

Overview

Journal Arterioscler Thromb Vasc Biol

Date 2014 Nov 1

PMID 25359855

Citations 6

Authors

John C Kostyak

Dheeraj Bhavanasi

Elisabeta Liverani

Steven E McKenzie

Satya P Kunapuli

Affiliations

Soon will be listed here.

Abstract

Objective: We previously determined that protein kinase C δ (PKCδ) regulates platelet function. However, the function of PKCδ in megakaryopoiesis is unknown.

Approach And Results: Using PKCδ(-/-) and wild-type littermate mice, we found that deficiency of PKCδ caused an increase in white blood cells and platelet counts, as well as in bone marrow and splenic megakaryocytes (P<0.05). Additionally, the megakaryocyte number and DNA content were enhanced in PKCδ(-/-) mouse bone marrow after culturing with exogenous thrombopoietin compared with wild-type (P<0.05). Importantly, thrombopoietin-induced signaling was also altered with PKCδ deletion because both extracellular signal-regulated kinase and Akt308 phosphorylation were heightened in PKCδ(-/-) megakaryocytes compared with wild-type. Finally, PKCδ(-/-) mice recovered faster and had a heightened rebound thrombocytosis after thrombocytopenic challenge.

Conclusions: These data suggest that PKCδ is an important megakaryopoietic protein, which regulates signaling induced by thrombopoietin and represents a potential therapeutic target.

Citing Articles

Characterization of Integrin αIIbβ3-Mediated Outside-in Signaling by Protein Kinase Cδ in Platelets.

Chaudhary P, Kim S, Jee Y, Lee S, Kim S Int J Mol Sci. 2020; 21(18).

PMID: 32911704 PMC: 7555476. DOI: 10.3390/ijms21186563.

Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis.

Liverani E, Mondrinos M, Sun S, Kunapuli S, Kilpatrick L PLoS One. 2018; 13(4):e0195379.

PMID: 29617417 PMC: 5884571. DOI: 10.1371/journal.pone.0195379.

PKC-epsilon deficiency alters progenitor cell populations in favor of megakaryopoiesis.

Kostyak J, Liverani E, Kunapuli S PLoS One. 2017; 12(8):e0182867.

PMID: 28783756 PMC: 5544228. DOI: 10.1371/journal.pone.0182867.

Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders.

Ringvold H, Khalil R Adv Pharmacol. 2017; 78:203-301.

PMID: 28212798 PMC: 5319769. DOI: 10.1016/bs.apha.2016.06.002.

Lung injury during LPS-induced inflammation occurs independently of the receptor P2Y.

Liverani E Purinergic Signal. 2016; 13(1):119-125.

PMID: 27815804 PMC: 5334203. DOI: 10.1007/s11302-016-9543-2.

References

Hong Y, Martin J, Vainchenker W, Erusalimsky J . Inhibition of protein kinase C suppresses megakaryocytic differentiation and stimulates erythroid differentiation in HEL cells. Blood. 1996; 87(1):123-31. View

Kato T, Ogami K, Shimada Y, Iwamatsu A, Sohma Y, Akahori H . Purification and characterization of thrombopoietin. J Biochem. 1995; 118(1):229-36. DOI: 10.1093/oxfordjournals.jbchem.a124883. View

Ballen K, Ritchie A, Murphy C, Handin R, Ewenstein B . Expression and activation of protein kinase C isoforms in a human megakaryocytic cell line. Exp Hematol. 1996; 24(13):1501-8. View

Liu R, Fan C, Garcia R, Jove R, Zuckerman K . Constitutive activation of the JAK2/STAT5 signal transduction pathway correlates with growth factor independence of megakaryocytic leukemic cell lines. Blood. 1999; 93(7):2369-79. View

Drachman J, Millett K, Kaushansky K . Thrombopoietin signal transduction requires functional JAK2, not TYK2. J Biol Chem. 1999; 274(19):13480-4. DOI: 10.1074/jbc.274.19.13480. View

Marchisio M, Bertagnolo V, Celeghini C, Vitale M, Capitani S, Zauli G . Selective modulation of specific protein kinase C (PKC) isoforms in primary human megakaryocytic vs. erythroid cells. Anat Rec. 1999; 255(1):7-14. DOI: 10.1002/(SICI)1097-0185(19990501)255:1<7::AID-AR2>3.0.CO;2-T. View

Rojnuckarin P, Drachman J, Kaushansky K . Thrombopoietin-induced activation of the mitogen-activated protein kinase (MAPK) pathway in normal megakaryocytes: role in endomitosis. Blood. 1999; 94(4):1273-82. View

Oshevski S, Le Bousse-Kerdiles M, Clay D, Levashova Z, Debili N, Vitral N . Differential expression of protein kinase C isoform transcripts in human hematopoietic progenitors undergoing differentiation. Biochem Biophys Res Commun. 1999; 263(3):603-9. DOI: 10.1006/bbrc.1999.1425. View

Lannutti B, Minear J, Blake N, Drachman J . Increased megakaryocytopoiesis in Lyn-deficient mice. Oncogene. 2006; 25(23):3316-24. DOI: 10.1038/sj.onc.1209351. View

10.

Italiano Jr J, Patel-Hett S, Hartwig J . Mechanics of proplatelet elaboration. J Thromb Haemost. 2007; 5 Suppl 1:18-23. DOI: 10.1111/j.1538-7836.2007.02487.x. View

11.

Gobbi G, Mirandola P, Sponzilli I, Micheloni C, Malinverno C, Cocco L . Timing and expression level of protein kinase C epsilon regulate the megakaryocytic differentiation of human CD34 cells. Stem Cells. 2007; 25(9):2322-9. DOI: 10.1634/stemcells.2006-0839. View

12.

Hitchcock I, Fox N, Prevost N, Sear K, Shattil S, Kaushansky K . Roles of focal adhesion kinase (FAK) in megakaryopoiesis and platelet function: studies using a megakaryocyte lineage specific FAK knockout. Blood. 2007; 111(2):596-604. PMC: 2200856. DOI: 10.1182/blood-2007-05-089680. View

13.

Nakao T, Geddis A, Fox N, Kaushansky K . PI3K/Akt/FOXO3a pathway contributes to thrombopoietin-induced proliferation of primary megakaryocytes in vitro and in vivo via modulation of p27(Kip1). Cell Cycle. 2008; 7(2):257-66. DOI: 10.4161/cc.7.2.5148. View

14.

Papadantonakis N, Makitalo M, McCrann D, Liu K, Nguyen H, Martin G . Direct visualization of the endomitotic cell cycle in living megakaryocytes: differential patterns in low and high ploidy cells. Cell Cycle. 2008; 7(15):2352-6. PMC: 2861775. DOI: 10.4161/cc.6325. View

15.

Lordier L, Jalil A, Aurade F, Larbret F, Larghero J, Debili N . Megakaryocyte endomitosis is a failure of late cytokinesis related to defects in the contractile ring and Rho/Rock signaling. Blood. 2008; 112(8):3164-74. DOI: 10.1182/blood-2008-03-144956. View

16.

Chari R, Getz T, Nagy Jr B, Bhavaraju K, Mao Y, Bynagari Y . Protein kinase C[delta] differentially regulates platelet functional responses. Arterioscler Thromb Vasc Biol. 2009; 29(5):699-705. PMC: 2742914. DOI: 10.1161/ATVBAHA.109.184010. View

17.

Chari R, Kim S, Murugappan S, Sanjay A, Daniel J, Kunapuli S . Lyn, PKC-delta, SHIP-1 interactions regulate GPVI-mediated platelet-dense granule secretion. Blood. 2009; 114(14):3056-63. PMC: 2756209. DOI: 10.1182/blood-2008-11-188516. View

18.

Lakhanpal G, Vecchiarelli-Federico L, Li Y, Cui J, Bailey M, Spaner D . The inositol phosphatase SHIP-1 is negatively regulated by Fli-1 and its loss accelerates leukemogenesis. Blood. 2010; 116(3):428-36. DOI: 10.1182/blood-2009-10-250217. View

19.

Kostyak J, Naik M, Naik U . Calcium- and integrin-binding protein 1 regulates megakaryocyte ploidy, adhesion, and migration. Blood. 2011; 119(3):838-46. PMC: 3265206. DOI: 10.1182/blood-2011-04-346098. View

20.

Salzer E, Santos-Valente E, Klaver S, Ban S, Emminger W, Prengemann N . B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ. Blood. 2013; 121(16):3112-6. PMC: 3630826. DOI: 10.1182/blood-2012-10-460741. View