Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1998 Aug 3;17(15):4391–4403. doi: 10.1093/emboj/17.15.4391

A beta 1 integrin signaling pathway involving Src-family kinases, Cbl and PI-3 kinase is required for macrophage spreading and migration.

F Meng 1, C A Lowell 1
PMCID: PMC1170772  PMID: 9687507

Abstract

We have used mutant macrophages which are deficient in expression of Src-family kinases to define an integrin signaling pathway that is required for macrophage adhesion and migration. Following ligation of surface integrins by fibronectin, the p120(c-cbl) (Cbl) protein rapidly becomes tyrosine phosphorylated and associated with the Src-family kinases Fgr and Lyn. In hck-/-fgr-/-lyn-/- triple mutant cells, which are defective in spreading on fibronectin-coated surfaces in vitro and show impaired migration in vivo, Cbl tyrosine phosphorylation is blocked, Cbl protein levels are low, adhesion-dependent translocation of Cbl to the membrane is impaired and Cbl-associated, membrane-localized phosphatidylinositol 3 (PI-3)-kinase activity is dramatically reduced. In contrast, adhesion-dependent activation of total cellular PI-3 kinase activity is normal in mutant cells, demonstrating that it is the membrane-associated fraction of PI-3 kinase which is most critical in regulating actin cytoskeletal rearrangements that lead to cell spreading. Treatment of wild-type cells with the Src-family-specific inhibitor PP1, Cbl antisense oligonucleotides or pharmacological inhibitors of PI-3 kinase blocks cell spreading on fibronectin surfaces. These data provide a molecular description for the role of Src-family kinases Hck, Fgr and Lyn in beta 1-integrin signal transduction in macrophages.

Full Text

The Full Text of this article is available as a PDF (523.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson S. M., Burton E. A., Koch B. L. Phosphorylation of Cbl following stimulation with interleukin-3 and its association with Grb2, Fyn, and phosphatidylinositol 3-kinase. J Biol Chem. 1997 Jan 10;272(2):739–745. doi: 10.1074/jbc.272.2.739. [DOI] [PubMed] [Google Scholar]
  2. Beggs H. E., Soriano P., Maness P. F. NCAM-dependent neurite outgrowth is inhibited in neurons from Fyn-minus mice. J Cell Biol. 1994 Nov;127(3):825–833. doi: 10.1083/jcb.127.3.825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berton G., Fumagalli L., Laudanna C., Sorio C. Beta 2 integrin-dependent protein tyrosine phosphorylation and activation of the FGR protein tyrosine kinase in human neutrophils. J Cell Biol. 1994 Aug;126(4):1111–1121. doi: 10.1083/jcb.126.4.1111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berton G., Yan S. R., Fumagalli L., Lowell C. A. Neutrophil activation by adhesion: mechanisms and pathophysiological implications. Int J Clin Lab Res. 1996;26(3):160–177. doi: 10.1007/BF02592978. [DOI] [PubMed] [Google Scholar]
  5. Bockholt S. M., Burridge K. Cell spreading on extracellular matrix proteins induces tyrosine phosphorylation of tensin. J Biol Chem. 1993 Jul 15;268(20):14565–14567. [PubMed] [Google Scholar]
  6. Bowtell D. D., Langdon W. Y. The protein product of the c-cbl oncogene rapidly complexes with the EGF receptor and is tyrosine phosphorylated following EGF stimulation. Oncogene. 1995 Oct 19;11(8):1561–1567. [PubMed] [Google Scholar]
  7. Boyce B. F., Yoneda T., Lowe C., Soriano P., Mundy G. R. Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J Clin Invest. 1992 Oct;90(4):1622–1627. doi: 10.1172/JCI116032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Burridge K., Turner C. E., Romer L. H. Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly. J Cell Biol. 1992 Nov;119(4):893–903. doi: 10.1083/jcb.119.4.893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chan V. W., Lowell C. A., DeFranco A. L. Defective negative regulation of antigen receptor signaling in Lyn-deficient B lymphocytes. Curr Biol. 1998 May 7;8(10):545–553. doi: 10.1016/s0960-9822(98)70223-4. [DOI] [PubMed] [Google Scholar]
  10. Chan V. W., Meng F., Soriano P., DeFranco A. L., Lowell C. A. Characterization of the B lymphocyte populations in Lyn-deficient mice and the role of Lyn in signal initiation and down-regulation. Immunity. 1997 Jul;7(1):69–81. doi: 10.1016/s1074-7613(00)80511-7. [DOI] [PubMed] [Google Scholar]
  11. Chen Q., Kinch M. S., Lin T. H., Burridge K., Juliano R. L. Integrin-mediated cell adhesion activates mitogen-activated protein kinases. J Biol Chem. 1994 Oct 28;269(43):26602–26605. [PubMed] [Google Scholar]
  12. Crowley M. T., Costello P. S., Fitzer-Attas C. J., Turner M., Meng F., Lowell C., Tybulewicz V. L., DeFranco A. L. A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages. J Exp Med. 1997 Oct 6;186(7):1027–1039. doi: 10.1084/jem.186.7.1027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. De Nichilo M. O., Yamada K. M. Integrin alpha v beta 5-dependent serine phosphorylation of paxillin in cultured human macrophages adherent to vitronectin. J Biol Chem. 1996 May 3;271(18):11016–11022. doi: 10.1074/jbc.271.18.11016. [DOI] [PubMed] [Google Scholar]
  14. Donovan J. A., Wange R. L., Langdon W. Y., Samelson L. E. The protein product of the c-cbl protooncogene is the 120-kDa tyrosine-phosphorylated protein in Jurkat cells activated via the T cell antigen receptor. J Biol Chem. 1994 Sep 16;269(37):22921–22924. [PubMed] [Google Scholar]
  15. Eberle M., Traynor-Kaplan A. E., Sklar L. A., Norgauer J. Is there a relationship between phosphatidylinositol trisphosphate and F-actin polymerization in human neutrophils? J Biol Chem. 1990 Oct 5;265(28):16725–16728. [PubMed] [Google Scholar]
  16. Frenette P. S., Mayadas T. N., Rayburn H., Hynes R. O., Wagner D. D. Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins. Cell. 1996 Feb 23;84(4):563–574. doi: 10.1016/s0092-8674(00)81032-6. [DOI] [PubMed] [Google Scholar]
  17. Galisteo M. L., Dikic I., Batzer A. G., Langdon W. Y., Schlessinger J. Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation. J Biol Chem. 1995 Sep 1;270(35):20242–20245. doi: 10.1074/jbc.270.35.20242. [DOI] [PubMed] [Google Scholar]
  18. Gold M. R., Chan V. W., Turck C. W., DeFranco A. L. Membrane Ig cross-linking regulates phosphatidylinositol 3-kinase in B lymphocytes. J Immunol. 1992 Apr 1;148(7):2012–2022. [PubMed] [Google Scholar]
  19. Hambleton J., McMahon M., DeFranco A. L. Activation of Raf-1 and mitogen-activated protein kinase in murine macrophages partially mimics lipopolysaccharide-induced signaling events. J Exp Med. 1995 Jul 1;182(1):147–154. doi: 10.1084/jem.182.1.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hanke J. H., Gardner J. P., Dow R. L., Changelian P. S., Brissette W. H., Weringer E. J., Pollok B. A., Connelly P. A. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J Biol Chem. 1996 Jan 12;271(2):695–701. doi: 10.1074/jbc.271.2.695. [DOI] [PubMed] [Google Scholar]
  21. Hartwig J. H., Kung S., Kovacsovics T., Janmey P. A., Cantley L. C., Stossel T. P., Toker A. D3 phosphoinositides and outside-in integrin signaling by glycoprotein IIb-IIIa mediate platelet actin assembly and filopodial extension induced by phorbol 12-myristate 13-acetate. J Biol Chem. 1996 Dec 20;271(51):32986–32993. doi: 10.1074/jbc.271.51.32986. [DOI] [PubMed] [Google Scholar]
  22. Haskill S., Beg A. A., Tompkins S. M., Morris J. S., Yurochko A. D., Sampson-Johannes A., Mondal K., Ralph P., Baldwin A. S., Jr Characterization of an immediate-early gene induced in adherent monocytes that encodes I kappa B-like activity. Cell. 1991 Jun 28;65(7):1281–1289. doi: 10.1016/0092-8674(91)90022-q. [DOI] [PubMed] [Google Scholar]
  23. Jongeward G. D., Clandinin T. R., Sternberg P. W. sli-1, a negative regulator of let-23-mediated signaling in C. elegans. Genetics. 1995 Apr;139(4):1553–1566. doi: 10.1093/genetics/139.4.1553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kaplan K. B., Bibbins K. B., Swedlow J. R., Arnaud M., Morgan D. O., Varmus H. E. Association of the amino-terminal half of c-Src with focal adhesions alters their properties and is regulated by phosphorylation of tyrosine 527. EMBO J. 1994 Oct 17;13(20):4745–4756. doi: 10.1002/j.1460-2075.1994.tb06800.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Khwaja A., Hallberg B., Warne P. H., Downward J. Networks of interaction of p120cbl and p130cas with Crk and Grb2 adaptor proteins. Oncogene. 1996 Jun 20;12(12):2491–2498. [PubMed] [Google Scholar]
  26. King W. G., Mattaliano M. D., Chan T. O., Tsichlis P. N., Brugge J. S. Phosphatidylinositol 3-kinase is required for integrin-stimulated AKT and Raf-1/mitogen-activated protein kinase pathway activation. Mol Cell Biol. 1997 Aug;17(8):4406–4418. doi: 10.1128/mcb.17.8.4406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Li J., Avraham H., Rogers R. A., Raja S., Avraham S. Characterization of RAFTK, a novel focal adhesion kinase, and its integrin-dependent phosphorylation and activation in megakaryocytes. Blood. 1996 Jul 15;88(2):417–428. [PubMed] [Google Scholar]
  28. Lin T. H., Aplin A. E., Shen Y., Chen Q., Schaller M., Romer L., Aukhil I., Juliano R. L. Integrin-mediated activation of MAP kinase is independent of FAK: evidence for dual integrin signaling pathways in fibroblasts. J Cell Biol. 1997 Mar 24;136(6):1385–1395. doi: 10.1083/jcb.136.6.1385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lin T. H., Yurochko A., Kornberg L., Morris J., Walker J. J., Haskill S., Juliano R. L. The role of protein tyrosine phosphorylation in integrin-mediated gene induction in monocytes. J Cell Biol. 1994 Sep;126(6):1585–1593. doi: 10.1083/jcb.126.6.1585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lowe C., Yoneda T., Boyce B. F., Chen H., Mundy G. R., Soriano P. Osteopetrosis in Src-deficient mice is due to an autonomous defect of osteoclasts. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4485–4489. doi: 10.1073/pnas.90.10.4485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lowell C. A., Berton G. Resistance to endotoxic shock and reduced neutrophil migration in mice deficient for the Src-family kinases Hck and Fgr. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7580–7584. doi: 10.1073/pnas.95.13.7580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lowell C. A., Fumagalli L., Berton G. Deficiency of Src family kinases p59/61hck and p58c-fgr results in defective adhesion-dependent neutrophil functions. J Cell Biol. 1996 May;133(4):895–910. doi: 10.1083/jcb.133.4.895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lowell C. A., Soriano P., Varmus H. E. Functional overlap in the src gene family: inactivation of hck and fgr impairs natural immunity. Genes Dev. 1994 Feb 15;8(4):387–398. doi: 10.1101/gad.8.4.387. [DOI] [PubMed] [Google Scholar]
  34. Manié S. N., Sattler M., Astier A., Phifer J. S., Canty T., Morimoto C., Druker B. J., Salgia R., Griffin J. D., Freedman A. S. Tyrosine phosphorylation of the product of the c-cbl protooncogene is [corrected] induced after integrin stimulation. Exp Hematol. 1997 Jan;25(1):45–50. [PubMed] [Google Scholar]
  35. Marcilla A., Rivero-Lezcano O. M., Agarwal A., Robbins K. C. Identification of the major tyrosine kinase substrate in signaling complexes formed after engagement of Fc gamma receptors. J Biol Chem. 1995 Apr 21;270(16):9115–9120. doi: 10.1074/jbc.270.16.9115. [DOI] [PubMed] [Google Scholar]
  36. Matsuo T., Hazeki K., Hazeki O., Katada T., Ui M. Specific association of phosphatidylinositol 3-kinase with the protooncogene product Cbl in Fc gamma receptor signaling. FEBS Lett. 1996 Mar 11;382(1-2):11–14. doi: 10.1016/0014-5793(96)00122-6. [DOI] [PubMed] [Google Scholar]
  37. Meng F., Lowell C. A. Lipopolysaccharide (LPS)-induced macrophage activation and signal transduction in the absence of Src-family kinases Hck, Fgr, and Lyn. J Exp Med. 1997 May 5;185(9):1661–1670. doi: 10.1084/jem.185.9.1661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Morino N., Mimura T., Hamasaki K., Tobe K., Ueki K., Kikuchi K., Takehara K., Kadowaki T., Yazaki Y., Nojima Y. Matrix/integrin interaction activates the mitogen-activated protein kinase, p44erk-1 and p42erk-2. J Biol Chem. 1995 Jan 6;270(1):269–273. doi: 10.1074/jbc.270.1.269. [DOI] [PubMed] [Google Scholar]
  39. Odai H., Sasaki K., Iwamatsu A., Hanazono Y., Tanaka T., Mitani K., Yazaki Y., Hirai H. The proto-oncogene product c-Cbl becomes tyrosine phosphorylated by stimulation with GM-CSF or Epo and constitutively binds to the SH3 domain of Grb2/Ash in human hematopoietic cells. J Biol Chem. 1995 May 5;270(18):10800–10805. doi: 10.1074/jbc.270.18.10800. [DOI] [PubMed] [Google Scholar]
  40. Ojaniemi M., Martin S. S., Dolfi F., Olefsky J. M., Vuori K. The proto-oncogene product p120(cbl) links c-Src and phosphatidylinositol 3'-kinase to the integrin signaling pathway. J Biol Chem. 1997 Feb 7;272(6):3780–3787. doi: 10.1074/jbc.272.6.3780. [DOI] [PubMed] [Google Scholar]
  41. Ota Y., Samelson L. E. The product of the proto-oncogene c-cbl: a negative regulator of the Syk tyrosine kinase. Science. 1997 Apr 18;276(5311):418–420. doi: 10.1126/science.276.5311.418. [DOI] [PubMed] [Google Scholar]
  42. Panchamoorthy G., Fukazawa T., Miyake S., Soltoff S., Reedquist K., Druker B., Shoelson S., Cantley L., Band H. p120cbl is a major substrate of tyrosine phosphorylation upon B cell antigen receptor stimulation and interacts in vivo with Fyn and Syk tyrosine kinases, Grb2 and Shc adaptors, and the p85 subunit of phosphatidylinositol 3-kinase. J Biol Chem. 1996 Feb 9;271(6):3187–3194. doi: 10.1074/jbc.271.6.3187. [DOI] [PubMed] [Google Scholar]
  43. Reddy S. A., Huang J. H., Liao W. S. Phosphatidylinositol 3-kinase in interleukin 1 signaling. Physical interaction with the interleukin 1 receptor and requirement in NFkappaB and AP-1 activation. J Biol Chem. 1997 Nov 14;272(46):29167–29173. doi: 10.1074/jbc.272.46.29167. [DOI] [PubMed] [Google Scholar]
  44. Roach T., Slater S., Koval M., White L., Cahir McFarland E. D., Okumura M., Thomas M., Brown E. CD45 regulates Src family member kinase activity associated with macrophage integrin-mediated adhesion. Curr Biol. 1997 Jun 1;7(6):408–417. doi: 10.1016/s0960-9822(06)00188-6. [DOI] [PubMed] [Google Scholar]
  45. Ross F. P., Chappel J., Alvarez J. I., Sander D., Butler W. T., Farach-Carson M. C., Mintz K. A., Robey P. G., Teitelbaum S. L., Cheresh D. A. Interactions between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integrin alpha v beta 3 potentiate bone resorption. J Biol Chem. 1993 May 5;268(13):9901–9907. [PubMed] [Google Scholar]
  46. Salgia R., Pisick E., Sattler M., Li J. L., Uemura N., Wong W. K., Burky S. A., Hirai H., Chen L. B., Griffin J. D. p130CAS forms a signaling complex with the adapter protein CRKL in hematopoietic cells transformed by the BCR/ABL oncogene. J Biol Chem. 1996 Oct 11;271(41):25198–25203. doi: 10.1074/jbc.271.41.25198. [DOI] [PubMed] [Google Scholar]
  47. Sattler M., Salgia R., Shrikhande G., Verma S., Uemura N., Law S. F., Golemis E. A., Griffin J. D. Differential signaling after beta1 integrin ligation is mediated through binding of CRKL to p120(CBL) and p110(HEF1). J Biol Chem. 1997 May 30;272(22):14320–14326. doi: 10.1074/jbc.272.22.14320. [DOI] [PubMed] [Google Scholar]
  48. Schaller M. D., Parsons J. T. Focal adhesion kinase and associated proteins. Curr Opin Cell Biol. 1994 Oct;6(5):705–710. doi: 10.1016/0955-0674(94)90097-3. [DOI] [PubMed] [Google Scholar]
  49. Shaw L. M., Rabinovitz I., Wang H. H., Toker A., Mercurio A. M. Activation of phosphoinositide 3-OH kinase by the alpha6beta4 integrin promotes carcinoma invasion. Cell. 1997 Dec 26;91(7):949–960. doi: 10.1016/s0092-8674(00)80486-9. [DOI] [PubMed] [Google Scholar]
  50. Smit L., van der Horst G., Borst J. Formation of Shc/Grb2- and Crk adaptor complexes containing tyrosine phosphorylated Cbl upon stimulation of the B-cell antigen receptor. Oncogene. 1996 Jul 18;13(2):381–389. [PubMed] [Google Scholar]
  51. Tanaka S., Amling M., Neff L., Peyman A., Uhlmann E., Levy J. B., Baron R. c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption. Nature. 1996 Oct 10;383(6600):528–531. doi: 10.1038/383528a0. [DOI] [PubMed] [Google Scholar]
  52. Tanaka S., Neff L., Baron R., Levy J. B. Tyrosine phosphorylation and translocation of the c-cbl protein after activation of tyrosine kinase signaling pathways. J Biol Chem. 1995 Jun 16;270(24):14347–14351. doi: 10.1074/jbc.270.24.14347. [DOI] [PubMed] [Google Scholar]
  53. Tezuka T., Umemori H., Fusaki N., Yagi T., Takata M., Kurosaki T., Yamamoto T. Physical and functional association of the cbl protooncogen product with an src-family protein tyrosine kinase, p53/56lyn, in the B cell antigen receptor-mediated signaling. J Exp Med. 1996 Feb 1;183(2):675–680. doi: 10.1084/jem.183.2.675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Thomas S. M., Soriano P., Imamoto A. Specific and redundant roles of Src and Fyn in organizing the cytoskeleton. Nature. 1995 Jul 20;376(6537):267–271. doi: 10.1038/376267a0. [DOI] [PubMed] [Google Scholar]
  55. Toker A., Cantley L. C. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature. 1997 Jun 12;387(6634):673–676. doi: 10.1038/42648. [DOI] [PubMed] [Google Scholar]
  56. Uddin S., Gardziola C., Dangat A., Yi T., Platanias L. C. Interaction of the c-cbl proto-oncogene product with the Tyk-2 protein tyrosine kinase. Biochem Biophys Res Commun. 1996 Aug 23;225(3):833–838. doi: 10.1006/bbrc.1996.1259. [DOI] [PubMed] [Google Scholar]
  57. Ueno H., Sasaki K., Miyagawa K., Honda H., Mitani K., Yazaki Y., Hirai H. Antisense repression of proto-oncogene c-Cbl enhances activation of the JAK-STAT pathway but not the ras pathway in epidermal growth factor receptor signaling. J Biol Chem. 1997 Mar 28;272(13):8739–8743. doi: 10.1074/jbc.272.13.8739. [DOI] [PubMed] [Google Scholar]
  58. Vuori K., Hirai H., Aizawa S., Ruoslahti E. Introduction of p130cas signaling complex formation upon integrin-mediated cell adhesion: a role for Src family kinases. Mol Cell Biol. 1996 Jun;16(6):2606–2613. doi: 10.1128/mcb.16.6.2606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Vuori K., Ruoslahti E. Tyrosine phosphorylation of p130Cas and cortactin accompanies integrin-mediated cell adhesion to extracellular matrix. J Biol Chem. 1995 Sep 22;270(38):22259–22262. doi: 10.1074/jbc.270.38.22259. [DOI] [PubMed] [Google Scholar]
  60. Wang Y., Yeung Y. G., Langdon W. Y., Stanley E. R. c-Cbl is transiently tyrosine-phosphorylated, ubiquitinated, and membrane-targeted following CSF-1 stimulation of macrophages. J Biol Chem. 1996 Jan 5;271(1):17–20. doi: 10.1074/jbc.271.1.17. [DOI] [PubMed] [Google Scholar]
  61. Xu H., Gonzalo J. A., St Pierre Y., Williams I. R., Kupper T. S., Cotran R. S., Springer T. A., Gutierrez-Ramos J. C. Leukocytosis and resistance to septic shock in intercellular adhesion molecule 1-deficient mice. J Exp Med. 1994 Jul 1;180(1):95–109. doi: 10.1084/jem.180.1.95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Yan S. R., Fumagalli L., Berton G. Activation of SRC family kinases in human neutrophils. Evidence that p58C-FGR and p53/56LYN redistributed to a Triton X-100-insoluble cytoskeletal fraction, also enriched in the caveolar protein caveolin, display an enhanced kinase activity. FEBS Lett. 1996 Feb 12;380(1-2):198–203. doi: 10.1016/0014-5793(96)00029-4. [DOI] [PubMed] [Google Scholar]
  63. Yoon C. H., Lee J., Jongeward G. D., Sternberg P. W. Similarity of sli-1, a regulator of vulval development in C. elegans, to the mammalian proto-oncogene c-cbl. Science. 1995 Aug 25;269(5227):1102–1105. doi: 10.1126/science.7652556. [DOI] [PubMed] [Google Scholar]
  64. van der Pluijm G., Mouthaan H., Baas C., de Groot H., Papapoulos S., Löwik C. Integrins and osteoclastic resorption in three bone organ cultures: differential sensitivity to synthetic Arg-Gly-Asp peptides during osteoclast formation. J Bone Miner Res. 1994 Jul;9(7):1021–1028. doi: 10.1002/jbmr.5650090709. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES