Direct binding of the EGF-like domain of neuregulin-1 to integrins (αvβ3 and α6β4) is involved in neuregulin-1/ErbB signaling

Katsuaki Ieguchi, Masaaki Fujita, Zi Ma, Parastoo Davari, Yukimasa Taniguchi, Kiyotoshi Sekiguchi, Bobby Wang, Yoko K. Takada, Yoshikazu Takada

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Integrin-growth factor receptor cross-talk plays a role in growth factor signaling, but the specifics are unclear. In a current model, integrins and growth factor receptors independently bind to their ligands (extracellular matrix and growth factors, respectively).Wediscovered that neuregulin-1 (NRG1), either as an isolated EGF-like domain or as a native multi-domain form, binds to integrins αvβ3 (with a KD of 1.36×10-7 M) and α6β4. Docking simulation predicted that three Lys residues at positions 180, 184, and 186 of the EGF-like domain are involved in integrin binding. Mutating these residues to Glu individually or in combination markedly suppressed integrin binding and ErbB3 phosphorylation. Mutating all three Lys residues to Glu (the 3KE mutation) did not affect the ability of NRG1 to bind to ErbB3 but markedly reduced the ability of NRG1 to induce ErbB3 phosphorylation and AKT and Erk1/2 activation in MCF-7 and T47D human breast cancer cells. This suggests that direct integrin binding to NRG1 is critical for NRG1/ErbB signaling. Notably, stimulation of cells with WT NRG1 induced co-precipitation of ErbB3 with α6β4 and with αvβ3 to a much lower extent. This suggests that WT NRG1 induces integrin-NRG1-ErbB3 ternary complex formation. In contrast, the 3KE mutant was much less effective in inducing ternary complex formation than WTNRG1, suggesting that this process depends on the ability of NRG1 to bind to integrins. These results suggest that direct NRG1-integrin interaction mediates integrin-ErbB cross-talk and that α6β4 plays a major role in NRG-ErbB signaling in these cancer cells.

Original languageEnglish
Pages (from-to)31388-31398
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number41
DOIs
Publication statusPublished - Oct 8 2010
Externally publishedYes

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Neuregulin-1
Epidermal Growth Factor
Integrins
Phosphorylation
Growth Factor Receptors
Intercellular Signaling Peptides and Proteins
Receptor Cross-Talk
Cells
Coprecipitation
Extracellular Matrix
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Direct binding of the EGF-like domain of neuregulin-1 to integrins (αvβ3 and α6β4) is involved in neuregulin-1/ErbB signaling. / Ieguchi, Katsuaki; Fujita, Masaaki; Ma, Zi; Davari, Parastoo; Taniguchi, Yukimasa; Sekiguchi, Kiyotoshi; Wang, Bobby; Takada, Yoko K.; Takada, Yoshikazu.

In: Journal of Biological Chemistry, Vol. 285, No. 41, 08.10.2010, p. 31388-31398.

Research output: Contribution to journalArticle

Ieguchi, K, Fujita, M, Ma, Z, Davari, P, Taniguchi, Y, Sekiguchi, K, Wang, B, Takada, YK & Takada, Y 2010, 'Direct binding of the EGF-like domain of neuregulin-1 to integrins (αvβ3 and α6β4) is involved in neuregulin-1/ErbB signaling', Journal of Biological Chemistry, vol. 285, no. 41, pp. 31388-31398. https://doi.org/10.1074/jbc.M110.113878
Ieguchi, Katsuaki ; Fujita, Masaaki ; Ma, Zi ; Davari, Parastoo ; Taniguchi, Yukimasa ; Sekiguchi, Kiyotoshi ; Wang, Bobby ; Takada, Yoko K. ; Takada, Yoshikazu. / Direct binding of the EGF-like domain of neuregulin-1 to integrins (αvβ3 and α6β4) is involved in neuregulin-1/ErbB signaling. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 41. pp. 31388-31398.
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abstract = "Integrin-growth factor receptor cross-talk plays a role in growth factor signaling, but the specifics are unclear. In a current model, integrins and growth factor receptors independently bind to their ligands (extracellular matrix and growth factors, respectively).Wediscovered that neuregulin-1 (NRG1), either as an isolated EGF-like domain or as a native multi-domain form, binds to integrins αvβ3 (with a KD of 1.36×10-7 M) and α6β4. Docking simulation predicted that three Lys residues at positions 180, 184, and 186 of the EGF-like domain are involved in integrin binding. Mutating these residues to Glu individually or in combination markedly suppressed integrin binding and ErbB3 phosphorylation. Mutating all three Lys residues to Glu (the 3KE mutation) did not affect the ability of NRG1 to bind to ErbB3 but markedly reduced the ability of NRG1 to induce ErbB3 phosphorylation and AKT and Erk1/2 activation in MCF-7 and T47D human breast cancer cells. This suggests that direct integrin binding to NRG1 is critical for NRG1/ErbB signaling. Notably, stimulation of cells with WT NRG1 induced co-precipitation of ErbB3 with α6β4 and with αvβ3 to a much lower extent. This suggests that WT NRG1 induces integrin-NRG1-ErbB3 ternary complex formation. In contrast, the 3KE mutant was much less effective in inducing ternary complex formation than WTNRG1, suggesting that this process depends on the ability of NRG1 to bind to integrins. These results suggest that direct NRG1-integrin interaction mediates integrin-ErbB cross-talk and that α6β4 plays a major role in NRG-ErbB signaling in these cancer cells.",
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AU - Ma, Zi

AU - Davari, Parastoo

AU - Taniguchi, Yukimasa

AU - Sekiguchi, Kiyotoshi

AU - Wang, Bobby

AU - Takada, Yoko K.

AU - Takada, Yoshikazu

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