Abstract
The members of the Src kinase family are expressed in a wide variety of tissues, but some of them such as Blk, Hck, Fgr, Lck and Lyn are found primarily in hematopoietic cells. In the present study, we have undertaken experiments to test whether Src kinase cleavage and relocation is a general mechanism during induction of apoptosis. Our results indicate that Fyn and Lyn are efficiently cleaved in their unique region in hematopoietic cells undergoing apoptosis. Fyn cleavage occurred in Fas-stimulated Jurkat T cells but Fyn and Lyn were also processed in the SKW6.4 B cell line. Inhibition of caspases by Z-VAD-fmk or Ac-DEVD-CHO totally prevented Fyn and Lyn cleavage in both intact cells and in vitro. Fyn and Lyn but not Lck, Src and Hck were processed in vitro by human recombinant caspase 3 and by cellular extracts prepared from Fas-stimulated cells. Single mutation of Asp 19 or Asp 18 in the unique N-terminal domains of Fyn and Lyn respectively abolished their cleavage and relocation into the cytoplasm of apoptotic cells. When immunoprecipitated from COS cells N-terminal deleted Src kinases exhibited increased enzymatic kinase activity toward enolase. Thus, cleavage of Fyn and Lyn during induction of apoptosis represents a new mechanism for the regulation of Src kinases that may have important functional and physiological consequences.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Appleby MW, Gross JA, Cooke MP, Levin SD, Qian X, Perlmutter RM . 1992 Cell 70: 751–763
Atkinson EA, Ostergaard H, Kane K, Pinkoski MJ, Caputo A, Olszowy MW, Bleackley RC . 1996 J. Biol. Chem. 271: 5968–5971
Bertolotto C, Maulon L, Filippa N, Baier G, Auberger P . 2000a J. Biol. Chem. 275: 37246–37250
Bertolotto C, Ricci JE, Luciano F, Mari B, Chambard JC, Auberger P . 2000b J. Biol. Chem. 275: 12941–12947
Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC . 1998 Science 282: 1318–1321
Chan VW, Meng F, Soriano P, DeFranco AL, Lowell CA . 1997 Immunity 7: 69–81
Corey SJ, Anderson SM . 1999 Blood 93: 1–14
Denny MF, Patai B, Straus DB . 2000 Mol. Cell. Biol. 20: 1426–1435
Dymecki SM, Niederhuber JE, Desiderio SV . 1990 Science 247: 332–336
Gervais FG, Veillette A . 1995 Mol. Cell. Biol. 15: 2393–2401
Golden A, Nemeth SP, Brugge JS . 1986 Proc. Natl. Acad. Sci. USA 83: 852–856
Hengartner MO . 2000 Nature 407: 770–776
Imbert V, Rupec RA, Livolsi A, Pahl HL, Traenckner EB, Mueller-Dieckmann C, Farahifar D, Rossi B, Auberger P, Baeuerle PA, Peyron JF . 1996 Cell 86: 787–798
Jimenez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N . 2000 Nat. Med. 6: 41–48
Johnson TM, Williamson NA, Scholz G, Jaworowski A, Wettenhall RE, Dunn AR, Cheng HC . 2000 J. Biol. Chem. 275: 33353–33364
Katsuta H, Tsuji S, Niho Y, Kurosaki T, Kitamura D . 1998 J. Immunol. 160: 1547–1551
Kawakami Y, Furue M, Kawakami T . 1989 Oncogene 4: 389–391
Krueger J, Zhao YH, Murphy D, Sudol M . 1991 Oncogene 6: 933–940
Mari B, Checler F, Ponzio G, Peyron JF, Manie S, Farahifar D, Rossi B, Auberger P . 1992 EMBO J. 11: 3875–3885
Maruo A, Oishi I, Sada K, Nomi M, Kurosaki T, Minami Y, Yamamura H . 1999 Int. Immunol. 11: 1371–1380
Nicholson DW, Thornberry NA . 1997 Trends Biochem. Sci. 22: 299–306
Nunez G, Benedict MA, Hu Y, Inohara N . 1998 Oncogene 17: 3237–3245
Pleiman CM, Clark MR, Gauen LK, Winitz S, Coggeshall KM, Johnson GL, Shaw AS, Cambier JC . 1993 Mol. Cell. Biol. 13: 5877–5887
Qin S, Minami Y, Kurosaki T, Yamamura H . 1997 J. Biol. Chem. 272: 17994–17999
Ricci JE, Maulon L, Luciano F, Guerin S, Livolsi A, Mari B, Breittmayer JP, Peyron JF, Auberger P . 1999 Oncogene 18: 3963–3969
Ricci JE, Lang V, Luciano F, Belhacene N, Giordanengo V, Michel F, Bismuth G, Auberger P . 2001 FASEB J. in press
Rudd CE, Barber EK, Burgess KE, Hahn JY, Odysseos AD, Sy MS, Schlossman SF . 1991 Adv. Exp. Med. Biol. 292: 85–96
Sarosi GA, Thomas PM, Egerton M, Phillips AF, Kim KW, Bonvini E, Samelson LE . 1992 Int. Immunol. 4: 1211–1217
Scaffidi C, Fulda S, Srinivasan A, Friescu C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME . 1998 EMBO J. 17: 1675–1687
Schlessinger J . 2000 Cell 100: 293–296
Schwartzberg PL . 1998 Oncogene 17: 1463–1468
Sefton BM, Taddie JA . 1994 Curr. Opin. Immunol. 6: 372–379
Simon HU, Yousefi S, Dibbert B, Hebestreit H, Weber M, Branch DR, Blaser K, Levi-Schaffer F, Anderson GP . 1998 Blood 92: 547–557
Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang HG, Reed JC, Nicholson DW, Alnemri ES, Green DR, Martin SJ . 1999 J. Cell. Biol. 144: 281–292
Sudol M, Greulich H, Newman L, Sarkar A, Sukegawa J, Yamamoto T . 1993 Oncogene 8: 823–831
Thornberry NA, Lazebnik Y . 1998 Science 281: 1312–1316
Veillette A, Bookman MA, Horak EM, Samelson LE, Bolen JB . 1989 Nature 338: 257–259
Wang J, Koizumi T, Watanabe T . 1996 J. Exp. Med. 184: 831–838
Widmann C, Gibson S, Johnson GL . 1998 J. Biol. Chem. 273: 7141–7147
Willman CL, Stewart CC, Longacre TL, Head DR, Habbersett R, Ziegler SF, Perlmutter RM . 1991 Blood 77: 726–734
Wolf BB, Green DR . 1999 J. Biol. Chem. 274: 20049–20052
Xu W, Doshi A, Lei M, Eck MJ, Harrison SC . 1999 Mol. Cell. 3: 629–638
Yamanashi Y, Mori S, Yoshida M, Kishimoto T, Inoue K, Yamamoto T, Toyoshima K . 1989 Proc. Natl. Acad. Sci. USA 86: 6538–6542
Yi TL, Bolen JB, Ihle JN . 1991 Mol. Cell. Biol. 11: 2391–2398
Yurchak LK, Sefton BM . 1995 Mol. Cell. Biol. 15: 6914–6922
Zhao YH, Baker H, Walaas SI, Sudol M . 1991 Oncogene 6: 1725–1733
Acknowledgements
This work was supported by INSERM and the Ligue Nationale Contre le Cancer (Equipe labellisée LNC). The authors thank Bernard Mari for critical reading of the manuscript. We are indebted to Dr Sarah Courtneidge for providing p59Fyn and p60Src cDNAs, to Dr Victor Tybulewicz for the kind gift of p56Lyn cDNA and to Dr Yves Colette and Pr Daniel Olive for Hck cDNA.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Luciano, F., Ricci, JE. & Auberger, P. Cleavage of Fyn and Lyn in their N-terminal unique regions during induction of apoptosis: a new mechanism for Src kinase regulation. Oncogene 20, 4935–4941 (2001). https://doi.org/10.1038/sj.onc.1204661
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204661
Keywords
This article is cited by
-
Src Family Protein Kinase Controls the Fate of B Cells in Autoimmune Diseases
Inflammation (2021)
-
The oncogenic tyrosine kinase Lyn impairs the pro-apoptotic function of Bim
Oncogene (2018)
-
O-GlcNAcylation is required for B cell homeostasis and antibody responses
Nature Communications (2017)
-
Physiological functions and clinical implications of the N-end rule pathway
Frontiers of Medicine (2016)
-
Functions of the Lyn tyrosine kinase in health and disease
Cell Communication and Signaling (2012)