Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

c-Cbl facilitates fibronectin matrix production by v-Abl-transformed NIH3T3 cells via activation of small GTPases

Oncogene volume 20, pages 1739–1755 (2001)Cite this article

Abstract

The protooncogenic protein c-Cbl has been shown to act as a multivalent adaptor and a negative regulator of protein tyrosine kinase-mediated signaling. Recent studies have implicated it in the regulation of cell adhesion-related events. We have previously shown that c-Cbl facilitates adhesion and spreading of v-Abl-transformed fibroblasts, and that these effects are dependent on its tyrosine phosphorylation. However, the mechanisms mediating effects of c-Cbl on fibroblast adhesion remain poorly understood. In this study we demonstrate that the tyrosine phosphorylation-dependent effect of c-Cbl on adhesion of v-Abl-transformed fibroblasts is primarily mediated by an increase in fibronectin matrix deposition by these cells. This increase in fibronectin matrix deposition and, hence, in cell adhesion is dependent on cytoskeletal rearrangements induced by RhoA, Rac1 and, possibly, Rap1 activation caused by c-Cbl. The observed activation of these GTPases is mediated by the recruitment of phosphatidylinositol-3′ kinase, CrkL and Vav2 to the C-terminal tyrosine residues of c-Cbl. The results of this study also demonstrate that ubiquitination is essential for the observed effects of c-Cbl on fibronectin matrix production and cell adhesion.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11

Similar content being viewed by others

Abbreviations

BD:

binding domain

BDM:

3-butanedione 2-monoxime

ECM:

extracellular matrix

EGFP:

enhanced green fluorescent protein

FN:

fibronectin

GEF:

guanine nucleotide exchange factor

GST:

glutathione-S-transferase

HA:

hemagglutinin

mAb:

monoclonal antibody

PBS:

phosphate-buffered saline

PI-3′ kinase:

phosphatidylinositol-3′ kinase

PTK:

protein tyrosine kinase.

References

  • Akamatsu H, Ichihara-Tanaka K, Ozono K, Kamiike W, Matsuda H, Sekiguchi K . 1996 Cancer Res. 56: 4541–4546

  • Akiyama S . 1996 Hum. Cell 9: 181–186

  • Altun-Gultekin ZF, Chandriani S, Bougeret C, Ishizaki T, Narumiya S, de Graaf P, Van Bergen en Henegouwen P, Hanafusa H, Wagner JA, Birge RB . 1998 Mol. Cell. Biol. 18: 3044–3058

  • Andoniou CE, Lill NL, Thien CB, Lupher ML Jr., Ota S, Bowtell DD, Scaife RM, Langdon WY, Band H . 2000 Mol. Cell. Biol. 20: 851–867

  • Andoniou CE, Thien CB, Langdon WY . 1996 Oncogene 12: 1981–1989

  • Arai A, Nosaka Y, Kohsaka H, Miyasaka N, Miura O . 1999 Blood 93: 3713–3722

  • Bokoch GM, Wang Y, Bohl BP, Sells MA, Quilliam LA, Knaus UG . 1996 J. Biol. Chem. 271: 25746–25749

  • Christopher RA, Kowalczyk AP, McKeown-Longo PJ . 1997 J. Cell. Sci. 110: 569–581

  • Chrzanowska-Wodnicka M, Burridge K . 1996 J. Cell. Biol. 133: 1403–1415

  • Crespo P, Schuebel KE, Ostrom AA, Gutkind JS, Bustelo XR . 1997 Nature 385: 169–172

  • Feng J, Ito M, Ichikawa K, Isaka N, Nishikawa M, Hartshorne D, Nakano T . 1999 J. Biol. Chem. 274: 37385–37390

  • Feshchenko EA, Langdon WY, Tsygankov AY . 1998 J. Biol. Chem. 273: 8323–8331

  • Feshchenko EA, Shore SK, Tsygankov AY . 1999 Oncogene 18: 3703–3715

  • Franke B, Akkerman J-WN, Bos JL . 1997 EMBO J. 16: 252–259

  • Gotoh T, Hattori S, Nakamura S, Kitayama H, Noda M, Takai Y, Kaibuchi K, Matsui H, Hatase O, Takahashi H, Kurata T, Matsuda M . 1995 Mol. Cell. Biol. 15: 6746–6753

  • Gotoh T, Niino Y, Tokuda M, Hatase O, Nakamura S, Matsuda M, Hattori S . 1997 J. Biol. Chem. 272: 18602–18607

  • Henske E, Short M, Jozwiak S, Bovey C, Ramlakhan S, Haines J, Kwiatkowski D . 1995 Ann. Hum. Genet. 59: 25–37

  • Herzhoff K, Sollberg S, Huerkamp C, Krieg T, Eckes B . 1999 Br. J. Dermatol. 141: 218–223

  • Ichiba T, Kuraishi Y, Sakai O, Nagata S, Groffen J, Kurata T, Hattori S, Matsuda M . 1997 J. Biol. Chem. 272: 22215–22220

  • Ishizaki T, Uehata M, Tamechika I, Keel J, Nonomura K, Maekawa M, Narumiya S . 2000 Mol. Pharmacol. 57: 976–983

  • Jascur T, Gilman J, Mustelin T . 1997 J. Biol. Chem. 272: 14483–14488

  • Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC . 1999 Science 286: 309–312

  • Katagiri K, Hattori M, Minato N, Irie S, Takatsu K, Kinashi T . 2000 Mol. Cell. Biol. 20: 1956–1969

  • Kawano Y, Fukata Y, Oshiro N, Amano M, Nakamura T, Ito M, Matsumura F, Inagaki M, Kaibuchi K . 1999 J. Cell. Biol. 147: 1023–1037

  • Kawata M, Matsui Y, Kondo J, Hishida T, Teranishi Y, Takai Y . 1988 J. Biol. Chem. 263: 18965–18971

  • Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K . 1996 Science 273: 245–248

  • Kitayama H, Sugimoto Y, Matsuzaki T, Ikawa Y, Noda M . 1989 Cell 56: 77–84

  • Klein S, Bikfalvi A, Birkenmeier T, Giancotti F, Rifkin D . 1996 J. Biol. Chem. 271: 22583–22590

  • Kumar C, Ohashi K, NAgata K, Walsh A, Bar-Sagi D, Mizuno K . 1999 Ann. NY Acad. Sci. 886: 122–131

  • Lamb NJ, Fernandez A, Conti MA, Adelstein R, Glass DB, Welch WJ, Feramisco JR . 1988 J. Cell. Biol. 106: 1955–1971

  • Lee D, Goldberg A . 1998 Trends Cell. Biol. 8: 397–403

  • Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I, Lavi S, Iwai K, Reiss Y, Ciechanover A, Lipkowitz S, Yarden Y . 1999 Mol. Cell 4: 1029–1040

  • Levkowitz G, Waterman H, Zamir E, Kam Z, Oved S, Langdon WY, Beguinot L, Geiger B, Yarden Y . 1998 Genes Deve. 12: 3663–3674

  • Liu YC, Altman A . 1998 Cell. Signal. 10: 377–385

  • Liu YC, Elly C, Langdon WY, Altman A . 1997 J. Biol. Chem. 272: 168–173

  • Lupher Jr. ML, Rao N, Eck MJ, Band H . 1999 Immunol. Today 20: 375–382

  • Magnusson MK, Mosher DF . 1998 Arterioscl., Thromb. Vasc. Biol. 18: 1363–1370

  • Malcolm K, Elliott C, Exton J . 1996 J. Biol. Chem. 271: 13135–13139

  • Marengere LE, Mirtsos C, Kozieradzki I, Veillette A, Mak TW, Penninger JM . 1997 J. Immunol. 159: 70–76

  • McKillop D, Fortune N, Ranatunga K, Geeves M . 1994 J. Muscle Res. Cell. Motil. 15: 309–318

  • Meng F, Lowell CA . 1998 EMBO J. 17: 4391–4403

  • Merlo JJ, Romano G, Gordon SS, Feshchenko EA, Peng G, Henderson EE, Tsygankov AY . 1998 Anticancer Res. 18: 2389–2396

  • Miyake S, Lupher Jr. ML, Druker B, Band H . 1998 Proc. Natl. Acad. Sci. USA 95: 7927–7932

  • Nobes CD, Hall A . 1995 Cell 81: 53–62

  • Nobes CD, Hawkins P, Stephens L, Hall A . 1995 J. Cell. Sci. 108: 225–233

  • Ojaniemi M, Martin SS, Dolfi F, Olefsky JM, Vuori K . 1997 J. Biol. Chem. 272: 3780–3787

  • Ota S, Hazeki K, Rao N, Lupher Jr. ML, Andoniou CE, Druker B, Band H . 2000 J. Biol. Chem. 275: 414–422

  • Parizi M, Howard E, Tomasek J . 2000 Exp. Cell. Biol. 254: 210–220

  • Parker PJ . 1995 Curr. Biol. 5: 577–579

  • Quilliam LA, Lambert QT, Mickelson-Young LA, Westwick JK, Sparks AB, Kay BK, Jenkins NA, Gilbert DJ, Copeland NG, Der CJ . 1996 J. Biol. Chem. 271: 28772–28776

  • Rajaraman R, MacSween J, Murdock C . 1983 Exp. Cell. Biol. 51: 9–18

  • Reedquist KA, Bos JL . 1998 J. Biol. Chem. 273: 4944–4949

  • Reedquist KA, Ross E, Koop EA, Wolthuis RM, Zwartkruis FJ, van Kooyk Y, Salmon M, Buckley CD, Bos JL . 2000 J. Cell. Biol. 148: 1151–1158

  • Reid T, Furuyashiki T, Ishizaki T, Watanabe G, Watanabe N, Fujisawa K, Morii N, Madaule P, Narumiya S . 1996 J. Biol. Chem. 271: 13556–13560

  • Reif K, Nobes CD, Thomas G, Hall A, Cantrell DA . 1996 Curr. Biol. 6: 1445–1455

  • Ren X, Kiosses W, Schwartz M . 1999 EMBO J. 18: 578–585

  • Ridley AJ, Hall A . 1992 Cold Spring Harbor Symp. Quant. Biol. 57: 661–671

  • Ruoslahti E . 1996 Ann. Rev. Cell. Dev. Biol. 12: 697–715

  • Ruoslahti E . 1999 Adv. Cancer Res. 76: 1–20

  • Sander E, van Delft S, ten Klooster J, Reid T, van der Kammen R, Michiels F, Collard J . 1998 J. Cell. Biol. 143: 1385–1398

  • Scaife RM, Langdon WY . 2000 J. Cell. Sci. 113: 215–226

  • Scardigli R, Soddu S, Falcioni R, Crescenzi M, Cimino L, Sacchi A . 1996 Exp. Cell. Res. 227: 223–229

  • Schlaepfer DD, Hunter T . 1998 Trends. Cell. Biol. 8: 151–157

  • Schoenwaelder SM, Burridge K . 1999 Curr. Opin. Cell. Biol. 11: 274–286

  • Schuebel KE, Movilla N, Rosa JL, Bustelo XR . 1998 EMBO J. 17: 6608–6621

  • Tanaka M, Gupta R, Mayer BJ . 1995 Mol. Cell. Biol. 15: 6829–6837

  • Tapon N, Hall A . 1997 Curr. Opin. Cell Biol. 9: 86–92

  • Thien CB, Langdon WY . 1998 Immunol. Cell. Biol. 76: 473–482

  • Tsukamoto N, Hattori M, Yang H, Bos JL, Minato N . 1999 J. Biol. Chem. 274: 18463–18469

  • Tsygankov A, Mahajan S, Fincke J, Bolen J . 1996 J. Biol. Chem. 271: 27130–27137

  • Tsygankov AY, Broker BM, Emmrich F . 1992 Cell. Immunol. 140: 97–111

  • Tsygankov AY, Spana C, Rowley RB, Penhallow RC, Burkhardt AL, Bolen JB . 1994 J. Biol. Chem. 269: 7792–7800

  • Vaheri A, Alitalo K, Hedman K, Keski-Oja J, Kurkinen M, Wartiovaara J . 1978 Ann. N. Y. Acad. Sci. 312: 343–353

  • Vaheri A, Mosher D . 1978 Biochim. Biophys. Acta 516: 1–25

  • Volberg T, Geiger B, Citi S, Bershadsky AD . 1994 Cell Motil. Cytoskel. 29: 321–338

  • Von Willebrand M, Jascur T, Bonnefoy-Berard N, Yano H, Altman A, Matsuda Y, Mustelin T . 1996 Eur. J. Biochem. 235: 828–835

  • Walsh A, Dhanasekaran M, Bar-Sagi D, Kumar C . 1997 Oncogene 16: 2553–2560

  • Wang Y, Yeung YG, Stanley ER . 1999 J. Cell. Biochem. 72: 119–134

  • Waterman H, Levkowitz G, Alroy I, Yarden Y . 1999 J. Biol. Chem. 274: 22151–22154

  • Wilde C, Genth H, Aktories K, Just I . 2000 J. Biol. Chem. 275: 16478–16483

  • Wu C, Keivens VM, O'Toole TE, McDonald JA, Ginsberg MH . 1995 Cell 83: 715–724

  • Zell T, Warden CS, Chan AS, Cook ME, Dell CL, Hunt SW, 3rd, Shimizu Y . 1998 Curr. Biol. 8: 814–822

  • Zhang Q, Magnusson MK, Mosher DF . 1997 Mol. Biol. Cell 8: 1415–1425

  • Zhong C, Chrzanowska-Wodnicka M, Brown J, Shaub A, Belkin AM, Burridge K . 1998 J. Cell Biol. 141: 539–551

Download references

Acknowledgements

We thank Drs W Langdon, T Mustelin, K Reedquist and Y Yarden for invaluable discussions and providing reagents, Drs J Bos, J Chernoff, J Collard, C Kumar, B Mayer, L Quilliam, and R Schwartz for providing reagents, Drs C Marcinkiewicz, D Mosser, S Niewiarovski, and S Shore for many helpful suggestions, J Faust for helpful assistance with FACS, and G Harvey for excellent editorial help. This work was supported by the National Institutes of Health grant CA78499 (to AY Tsygankov).

Author information

Author notes

  1. Anjali M Teckchandani and Elena A Feshchenko: AM Teckchandani and EA Feshchenko made equal contributions to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, 19140, Pennsylvania, PA, USA

    Anjali M Teckchandani, Elena A Feshchenko & Alexander Y Tsygankov

Authors
  1. Anjali M Teckchandani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elena A Feshchenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander Y Tsygankov
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Teckchandani, A., Feshchenko, E. & Tsygankov, A. c-Cbl facilitates fibronectin matrix production by v-Abl-transformed NIH3T3 cells via activation of small GTPases. Oncogene 20, 1739–1755 (2001). https://doi.org/10.1038/sj.onc.1204246

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204246

Keywords

This article is cited by

Search

Advanced search

Quick links