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Horm Metab Res 2003; 35(4): 228-235
DOI: 10.1055/s-2003-39479
Original Basic
© Georg Thieme Verlag Stuttgart · New York

Prolactin Receptor Signaling during Platelet Activation

H.  Wallaschofski 1 , A.  Kobsar 4 , M.  Koksch 1 , A.  Siegemund 1 , B.  Hentschel 2 , U.  Tuschy 3 , T.  Lohmann 1 , O.  Sokolova 4 , M.  Eigenthaler 4
  • 1 Department of Internal Medicine I, University of Erlangen, Germany
  • 2 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany
  • 3 Department of Internal Medicine II, Hospital of Erfurt, Germany
  • 4 Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Germany
T. Lohmann, M. Eigenthaler, H. Wallaschofski and A. Kobsar contributed equally.
Further Information

Publication History

Received 2 July 2002

Accepted after Revision 10 September 2002

Publication Date:
02 June 2003 (online)

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Abstract

Prolactin is a newly recognized platelet coactivator that functions through potentiation of ADP-induced platelet activation. However, the possible association between hyperprolactinemia and venous thromboembolism (VTE) has not been systematically investigated up to now; prolactin signaling mechanisms in platelets still need to be elucidated. In this study, plasma prolactin levels in healthy subjects and patients with VTE were determined, demonstrating that patients with VTE and no other congenital risk factors had significantly increased plasma prolactin levels. Moreover, prolactinoma patients demonstrated a higher incidence of VTE than the general population. To elucidate the molecular mechanisms for the development of venous thrombosis, prolactin receptor signaling during platelet activation was investigated with a focus on ADP-stimulated G-protein-regulated signaling pathways. The short isoform of prolactin receptors was detected on platelets. Signaling through this receptor, although not directly linked to Gq-proteins, substitutes for Gq-protein regulated signaling pathways involved in platelet activation. We identified protein kinase C, a well-established signaling molecule in platelet activation, as a target molecule for prolactin signaling pathways in human platelets. Our findings indicate that hyperprolactinemia may be an important novel risk factor for VTE, suggesting that its thrombogenic effect may be mediated through enhanced platelet reactivity. Revealing the molecular mechanisms of prolactin signaling will allow the design of new antithrombotic therapies.

Key words

Prolactin - Thrombosis - Platelet activation - G proteins - Protein kinase C - Pituitary tumor

References

  • 1 Heit J A, Silverstein M D, Mohr D N, Petterson T M, Lohse C M, O'Fallon W M, Melton L J. The epidemiology of venous thromboembolism in the community.  Thromb Haemost. 2001;  86 452-463
    PubMedGoogle Scholar
  • 2 Rosendaal F R. Venous thrombosis: a multicausal disease.  Lancet. 1999;  353 1167-1173
    CrossrefPubMedGoogle Scholar
  • 3 Rosendaal F R. Venous thrombosis: prevalence and interaction of risk factors.  Haemostasis. 1999;  29 Suppl S1 1-9
    PubMedGoogle Scholar
  • 4 Bates S M, Ginsberg J S. Thrombosis in pregnancy.  Curr Opin Hematol. 1997;  4 335-343
    PubMedGoogle Scholar
  • 5 Greer I A. Thrombosis in pregnancy: maternal and fetal issues.  Lancet. 1999;  353 1258-1265
    CrossrefPubMedGoogle Scholar
  • 6 Wallaschofski H, Donné M, Eigenthaler M, Hentschel B, Faber R, Stepan H, Koksch M, Lohmann T. Prolactin as a novel potent cofactor for platelet aggregation.  J Clin Endocrinol Metab. 2001;  86 5912-5919
    CrossrefPubMedGoogle Scholar
  • 7 David S R, Taylor C C, Kinon B J, Breier A. The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia.  Clin Ther. 2000;  22 1085-1096
    CrossrefPubMedGoogle Scholar
  • 8 Zornberg G L, Jick H. Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study.  Lancet. 2000;  356 1219-1223
    CrossrefPubMedGoogle Scholar
  • 9 Tripodi A, Mannucci P M. Laboratory investigation of thrombophilia.  Clin Chem. 2001;  47 1597-1606
    PubMedGoogle Scholar
  • 10 Schwarz U R, Geiger J, Walter U, Eigenthaler M. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets-definition and detection of ticlopidine/clopidogrel effects.  Thromb Haemost. 1999;  82 1145-1152
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Geiger J, Honig-Liedl P, Schanzenbacher P, Walter U. Ligand specificity and ticlopidine effects distinguish three human platelet ADP receptors.  Eur J Pharmacol. 1998;  351 235-246
    CrossrefPubMedGoogle Scholar
  • 12 Oger E. Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d'Etude de la Thrombose de Bretagne Occidentale.  Thromb Haemost. 2000;  83 657-660
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 White R H, Zhou H, Romano P S. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California.  Ann Intern Med. 1998;  128 737-740
    CrossrefPubMedGoogle Scholar
  • 14 Bellone G, Geuna M, Carbone A, Silvestri S, Foa R, Emanuelli G, Matera L. Regulatory action of prolactin on the in vitro growth of CD34+ human hemopoietic progenitor cells.  J Cell Physiol. 1995;  163 221-231
    CrossrefPubMedGoogle Scholar
  • 15 Draca S. Prolactin as an immunoreactive agent.  Immunol Cell Biol. 1995;  73 481-483
    PubMedGoogle Scholar
  • 16 Jin J, Kunapuli S P. Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation.  Proc Natl Acad Sci U S A. 1998;  95 8070-8074
    CrossrefPubMedGoogle Scholar
  • 17 Savi P, Beauverger P, Labouret C, Delfaud M, Salel V, Kaghad M, Herbert J M. Role of P2Y1 purinoceptor in ADP-induced platelet activation.  FEBS Lett. 1998;  422 291-295
    CrossrefPubMedGoogle Scholar
  • 18 Daniel J L, Dangelmaier C, Jin J, Kim Y B, Kunapuli S P. Role of intracellular signaling events in ADP-induced platelet aggregation.  Thromb Haemost. 1999;  82 1322-1326
    PubMedGoogle Scholar
  • 19 Keranen L M, Dutil E M, Newton A C. Protein kinase C is regulated in vivo by three functionally distinct phosphorylations.  Curr Biol. 1995;  5 1394-1403
    CrossrefPubMedGoogle Scholar
  • 20 Jin J, Daniel J L, Kunapuli S P. Molecular basis for ADP-induced platelet activation. II. The P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets.  J Biol Chem. 1998;  273 2030-2034
    CrossrefPubMedGoogle Scholar
  • 21 Celi A, Lorenzet R, Furie B, Furie B C. Platelet-leukocyte-endothelial cell interaction on the blood vessel wall.  Semin Hematol. 1997;  34 327-335
    PubMedGoogle Scholar
  • 22 Merten M, Thiagarajan P. P-selectin expression on platelets determines size and stability of platelet aggregates.  Circulation. 2000;  102 1931-1936
    PubMedGoogle Scholar
  • 23 Pulmonary Embolism Prevention trial  . Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial.  Lancet. 2000;  355 1295-1302
    CrossrefPubMedGoogle Scholar
  • 24 Collins R, Baigent C, Sandercock P, Peto R. Antiplatelet therapy for thromboprophylaxis: the need for careful consideration of the evidence from randomised trials. Antiplatelet Trialists'.  Bmj. 1994;  309 1215-1217
    PubMedGoogle Scholar
  • 25 Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy-III: . Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients.  BMJ. 1994;  308 235-246
    Google Scholar
  • 26 Molitch M E, Thorner M O, Wilson C. Management of prolactinomas.  J Clin Endocrinol Metab. 1997;  82 996-1000
    CrossrefPubMedGoogle Scholar
  • 27 Nagano M, Kelly P A. Tissue distribution and regulation of rat prolactin receptor gene expression. Quantitative analysis by polymerase chain reaction.  J Biol Chem. 1994;  269 13 337-13 345
    PubMedGoogle Scholar
  • 28 Postel-Vinay M C. Growth hormone- and prolactin-binding proteins: soluble forms of receptors.  Horm Res. 1996;  45 178-181
    PubMedGoogle Scholar
  • 29 Dardenne M, de Moraes M, Kelly P A, Gagnerault M C. Prolactin receptor expression in human hematopoietic tissues analyzed by flow cytofluorometry.  Endocrinology. 1994;  134 2108-2114
    CrossrefPubMedGoogle Scholar
  • 30 Rui H, Kirken R A, Farrar W L. Activation of receptor-associated tyrosine kinase JAK2 by prolactin.  J Biol Chem. 1994;  269 5364-5368
    PubMedGoogle Scholar
  • 31 Goffin V, Kelly P A. The prolactin/growth hormone receptor family: structure/function relationships.  J Mammary Gland Biol. Neoplasia 1997;  2 7-17
    PubMedGoogle Scholar
  • 32 Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly P A. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice.  Endocr Rev. 1998;  19 225-268
    CrossrefPubMedGoogle Scholar
  • 33 Frank D A. STAT signaling in the pathogenesis and treatment of cancer.  Mol Med. 1999;  5 432-456
    PubMedGoogle Scholar
  • 34 Rao Y P, Buckley D J, Buckley A R. Rapid activation of mitogen-activated protein kinase and p21ras by prolactin and interleukin 2 in rat Nb2 node lymphoma cells.  Cell Growth Differ. 1995;  6 1235-1244
    PubMedGoogle Scholar
  • 35 Erwin R A, Kirken R A, Malabarba M G, Farrar W L, Rui H. Prolactin activates Ras via signaling proteins SHC, growth factor receptor bound 2, and son of sevenless.  Endocrinology. 1995;  136 3512-3518
    CrossrefPubMedGoogle Scholar
  • 36 Clevenger C V, Torigoe T, Reed J C. Prolactin induces rapid phosphorylation and activation of prolactin receptor-associated RAF-1 kinase in a T-cell line.  J Biol Chem. 1994;  269 5559-5565
    PubMedGoogle Scholar
  • 37 Peters C A, Maizels E T, Robertson M C, Shiu R P, Soloff M S, Hunzicker-Dunn M. Induction of relaxin messenger RNA expression in response to prolactin receptor activation requires protein kinase C delta signaling.  Mol Endocrinol. 2000;  14 576-590
    CrossrefPubMedGoogle Scholar
  • 38 Rao Y P, Buckley D J, Olson M D, Buckley A R. Nuclear translocation of prolactin: collaboration of tyrosine kinase and protein kinase C activation in rat Nb2 node lymphoma cells.  J Cell Physiol. 1995;  163 266-276
    CrossrefPubMedGoogle Scholar
  • 39 Vacher P, Tran V an, Paly J, Djiane J, Dufy B. Short term effect of prolactin on intracellular calcium in Chinese hamster ovary cells stably transfected with prolactin receptor complementary deoxyribonucleic acid.  Endocrinology. 1994;  134 1213-1218
    CrossrefPubMedGoogle Scholar
  • 40 Larrea F, Sanchez-Gonzalez S, Mendez I, Garcia-Becerra R, Cabrera V, Ulloa-Aguirre A. G protein-coupled receptors as targets for prolactin actions.  Arch Med Res. 1999;  30 532-543
    CrossrefPubMedGoogle Scholar
  • 41 Johansen P W, Lund H W, Gordeladze J O. Specific combinations of G-protein subunits discriminate hormonal signalling in rat pituitary (GH(3)) cells in culture.  Cell Signal. 2001;  13 251-256
    CrossrefPubMedGoogle Scholar
  • 42 Kline J B, Moore D J, Clevenger C V. Activation and association of the Tec tyrosine kinase with the human prolactin receptor: mapping of a Tec/Vav1-receptor binding site.  Mol Endocrinol. 2001;  15 832-841
    CrossrefPubMedGoogle Scholar
  • 43 Daniel J L, Dangelmaier C, Jin J, Ashby B, Smith J B, and K unapuli. Molecular basis for ADP-induced platelet activation. I. Evidence for three distinct ADP receptors on human platelets.  J Biol Chem. 1998;  273 2024-2029
    CrossrefPubMedGoogle Scholar
  • 44 Tibbles H E, Vassilev A, Wendorf H, Schonhoff D, Zhu D, Lorenz D, Waurzyniak B, Liu X P, Uckun F M. Role of a JAK3-dependent biochemical signaling pathway in platelet activation and aggregation.  J Biol Chem. 2001;  276 17 815-17 822
    PubMedGoogle Scholar

T. Lohmann, MD

University of Erlangen · Department of Internal Medicine I

Krankenhausstraße 12 · 91054 Erlangen · Germany ·

Phone: +49 (913) 1 8536970

Fax: +49 (913) 1 8533428

Email: Tobias.Lohmann@med1.imed.uni-erlangen.de

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