Skip to main content

Reelin is a platelet protein and functions as a positive regulator of platelet spreading on fibrinogen


Abnormalities of platelet functions have been linked to reelin-impaired neuronal disorders. However, little attention has been given to understanding the interplay between reelin and platelet. In this study, reelin was found to present in the human platelets and megakaryocyte-like leukemic cells. Reelin-binding assays revealed that extracellular reelin can interact with platelets through the receptor belonging to the low density lipoprotein receptor gene family. The reelin-to-platelet interactions enhance platelet spreading on fibrinogen concomitant with the augmentation of lamellipodia formation and F-actin bundling. In contrast, reelin has no effect on integrin αIIbβ3 activation and agonist-induced platelet aggregation. Molecular analysis revealed that the up-regulation of Rac1 activity and the inhibition of protein kinase C δ-Thr505 phosphorylation are important for reelin-mediated enhancement of platelet spreading on fibrinogen. These findings demonstrate for the first time that reelin is present in platelets and the reelin-to-platelet interactions play a novel role in platelet signaling and functions.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6



Arachidonic acid


ApoE receptor 2


Bovine serum albumin




Fluorescein isothiocyanate




Peripheral blood mononuclear cell


Phosphate-buffered saline


Platelet factor 4


Protein kinase C δ

PGI2 :

Prostaglandin I2




Receptor-associated protein


SRC family tyrosine kinases


  1. 1.

    D’Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T (1995) A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374:719–723

    Article  PubMed  Google Scholar 

  2. 2.

    Quattrocchi CC, Wannenes F, Persico AM, Ciafre SA, D’Arcangelo G, Farace MG, Keller F (2002) Reelin is a serine protease of the extracellular matrix. J Biol Chem 277:303–309

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Assadi AH, Zhang G, Beffert U, McNeil RS, Renfro AL, Niu S, Quattrocchi CC, Antalffy BA, Sheldon M, Armstrong DD, Wynshaw-Boris A, Herz J, D’Arcangelo G, Clark GD (2003) Interaction of reelin signaling and Lis1 in brain development. Nat Genet 35:270–276

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Hiesberger T, Trommsdorff M, Howell BW, Goffinet A, Mumby MC, Cooper JA, Herz J (1999) Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron 24:481–489

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Bock HH, Herz J (2003) Reelin activates SRC family tyrosine kinases in neurons. Curr Biol 13:18–26

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Botella-Lopez A, Burgaya F, Gavin R, Garcia-Ayllon MS, Gomez-Tortosa E, Pena-Casanova J, Urena JM, Del Rio JA, Blesa R, Soriano E, Saez-Valero J (2006) Reelin expression and glycosylation patterns are altered in Alzheimer’s disease. Proc Natl Acad Sci USA 103:5573–5578

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Deutsch SI, Rosse RB, Lakshman RM (2006) Dysregulation of tau phosphorylation is a hypothesized point of convergence in the pathogenesis of alzheimer’s disease, frontotemporal dementia and schizophrenia with therapeutic implications. Prog Neuropsychopharmacol Biol Psychiatry 30:1369–1380

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Fatemi SH, Kroll JL, Stary JM (2001) Altered levels of Reelin and its isoforms in schizophrenia and mood disorders. Neuroreport 12:3209–3215

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Botella-Lopez A, de Madaria E, Jover R, Bataller R, Sancho-Bru P, Candela A, Compañ A, Pérez-Mateo M, Martinez S, Sáez-Valero J (2008) Reelin is overexpressed in the liver and plasma of bile duct ligated rats and its levels and glycosylation are altered in plasma of humans with cirrhosis. Int J Biochem Cell Biol 40:766–775

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Smalheiser NR, Costa E, Guidotti A, Impagnatiello F, Auta J, Lacor P, Kriho V, Pappas GD (2000) Expression of reelin in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells. Proc Natl Acad Sci USA 97:1281–1286

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Dietrich-Muszalska A, Olas B (2007) The changes of aggregability of blood platelets in schizophrenia. World J Biol Psychiatry 14:1–6

    Google Scholar 

  12. 12.

    Yao JK, van Kammen DP, Gurklis J, Peters JL (1994) Platelet aggregation and dense granule secretion in schizophrenia. Psychiatry Res 54:13–24

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Suzuki K, Kusumi I, Akimoto T, Sasaki Y, Koyama T (2003) Altered 5-HT-induced calcium response in the presence of staurosporine in blood platelets from bipolar disorder patients. Neuropsychopharmacology 28:1210–1214

    CAS  PubMed  Google Scholar 

  14. 14.

    Suzuki K, Kusumi I, Sasaki Y, Koyama T (2001) Serotonin-induced platelet intracellular calcium mobilization in various psychiatric disorders: is it specific to bipolar disorder? J Affect Disord 64:291–296

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Huang YJ, Chen IS, Tseng CP, Day YJ, Lin YC, Liao CH (2008) (2R, 3R)-2-(3′, 4′-dihydroxybenzyl)-3-(3″, 4″-dimethoxybenzyl)butyrolactone suppresses fMLP-induced superoxide production by inhibiting fMLP-receptor binding in human neutrophils. Biochem Pharmacol 75:688–697

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Medina C, Jurasz P, Santos-Martinez MJ, Jeong SS, Mitsky T, Chen R, Radomski MW (2006) Platelet aggregation-induced by caco-2 cells: regulation by matrix metalloproteinase-2 and adenosine diphosphate. J Pharmacol Exp Ther 317:739–745

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Huang CL, Cheng JC, Liao CH, Stern A, Hsieh JT, Wang CH, Hsu HL, Tseng CP (2004) Disabled-2 is a negative regulator of integrin αIIbβ3-mediated fibrinogen adhesion and cell signaling. J Biol Chem 279:42279–42289

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Lugli G, Krueger JM, Davis JM, Persico AM, Keller F, Smalheiser NR (2003) Methodological factors influencing measurement and processing of plasma reelin in human. BMC Biochem 4:9

    Article  PubMed  Google Scholar 

  19. 19.

    Huang CL, Cheng JC, Stern A, Hsieh JT, Liao CH, Tseng CP (2006) Disabled-2 is a novel αIIb-integrin-binding protein that negatively regulates platelet-fibrinogen interactions and platelet aggregation. J Cell Sci 119:4420–4429

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    D’Arcangelo G, Homayouni R, Keshvara L, Rice DS, Sheldon M, Curran T (1999) Reelin is a ligand for lipoprotein receptors. Neuron 24:471–479

    Article  PubMed  Google Scholar 

  21. 21.

    Huang CH, Cheng JC, Chen JC, Tseng CP (2007) Evaluation of the role of Disabled-2 in nerve growth factor-mediated neurite outgrowth and cellular signalling. Cell Signal 19:1339–1347

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Mairhofer M, Steiner M, Mosgoeller W, Prohaska R, Salzer U (2002) Stomatin is a major lipid-raft component of platelet α-granules. Blood 100:897–904

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Brandes C, Kahr L, Stockinger W, Hiesberger T, Schneider WJ, Nimpf J (2001) Alternative splicing in the ligand binding domain of mouse ApoE receptor-2 produces receptor variants binding reelin but not alpha 2-macroglobulin. J Biol Chem 276:22160–22169

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Pennings MT, Derksen RH, Urbanus RT, Tekelenburg WL, Hemrika W, de Groot PG (2007) Platelets express three different splice variants of ApoER2 that are all involved in signaling. J Thromb Haemost 5:1538–1544

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Bu G (1998) Receptor-associated protein: a specialized chaperone and antagonist for members of the LDL receptor gene family. Curr Opin Lipidol 9:149–155

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    McCarty OJ, Larson MK, Auger JM, Kalia N, Atkinson BT, Pearce AC, Ruf S, Henderson RB, Tybulewicz VL, Machesky LM, Watson SP (2005) Rac1 is essential for platelet lamellipodia formation and aggregate stability under flow. J Biol Chem 280:39474–39484

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Ogawa M, Miyata T, Nakajima K, Yagyu K, Seike M, Ikenaka K, Yamamoto H, Mikoshiba K (1995) The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neuron 14:899–912

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Miyata T, Nakajima K, Mikoshiba K, Ogawa M (1997) Regulation of Purkinje cell alignment by reelin as revealed with CR-50 antibody. J Neurosci 17:3599–3609

    CAS  PubMed  Google Scholar 

  29. 29.

    D’Arcangelo G, Nakajima K, Miyata T, Ogawa M, Mikoshiba K, Curran T (1997) Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody. J Neurosci 17:23–31

    PubMed  Google Scholar 

  30. 30.

    Del Rio JA, Heimrich B, Borrell V, Forster E, Drakew A, Alcantara S, Nakajima K, Miyata T, Ogawa M, Mikoshiba K, Derer P, Froyscher M, Soriano F (1997) A role of Cajai-Retzius cells and reelin in the development of hippocampal connections. Nautre 385:70–74

    CAS  Google Scholar 

  31. 31.

    Hartwig JH, Barkalow K, Azim A, Italiano J (1999) The elegant platelet: signals controlling actin assembly. Thromb Haemost 82:392–398

    CAS  PubMed  Google Scholar 

  32. 32.

    Harper MT, Poole AW (2007) Isoform-specific functions of protein kinase C: the platelet paradigm. Biochem Soc Trans 35:1005–1008

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Chen Z, Hu M, Shivdasani A (2007) Expression analysis of primary mouse megakaryocyte differentiation and its application in identifying stage-specific molecular markers and a novel transcriptional target of NF-E2. Blood 109:1451–1459

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Jirousková M, Jaiswal JK, Coller BS (2007) Ligand density dramatically affects integrin αIIbβ3-mediated platelet signaling and spreading. Blood 109:5260–5269

    Article  PubMed  Google Scholar 

  35. 35.

    Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K (2003) Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 9:61–67

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Pula G, Schuh K, Nakayama K, Nakayama KI, Walter U, Poole AW (2006) PKCdelta regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation. Blood 108:4035–4044

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Morimura T, Hattori M, Ogawa M, Mikoshiba K (2005) Disabled 1 regulates the intracellular trafficking of reelin receptors. J Biol Chem 280:16901–16908

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Cuitino L, Matute R, Retamal C, Bu G, Inestrosa NC, Marzolo MP (2005) ApoER2 is endocytosed by a clathrin-mediated process involving the adaptor protein Dab2 independent of its Rafts’ association. Traffic 6:820–838

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Urbanus RT, Pennings MTT, Derksen RHWM, De Groot PG (2008) Platelet activation by dimeric β2-glycoprotein I requires signaling via both glycoprotein Iba and apolipoprotein E receptor 2’. J Thromb Haemost 6:1405–1412

    Article  CAS  PubMed  Google Scholar 

Download references


This work was supported in part by the grants NHRI-EX98-9612BI, NSC 95-2320-B-182-023-MY3, CMRPD170132, EMRPD180171 and EMRPD180221 to C.P.T; CMU95-335 to J.C.C.

Author information



Corresponding authors

Correspondence to Ju-Chien Cheng or Ching-Ping Tseng.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Tseng, WL., Huang, CL., Chong, KY. et al. Reelin is a platelet protein and functions as a positive regulator of platelet spreading on fibrinogen. Cell. Mol. Life Sci. 67, 641–653 (2010).

Download citation


  • Fibrinogen
  • Platelet spreading
  • PKCδ
  • Rac1
  • Reelin