Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling

Yoshikazu Nakaoka, Keigo Nishida, Masahiro Narimatsu, Atsunori Kamiya, Takashi Minami, Hirofumi Sawa, Katsuya Okawa, Yasushi Fujio, Tatsuya Koyama, Makiko Maeda, Manami Sone, Satoru Yamasaki, Yuji Arai, Young Koh Gou, Tatsuhiko Kodama, Hisao Hirota, Kinya Otsu, Toshio Hirano, Naoki Mochizuki

Research output: Contribution to journalArticle

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Abstract

Grb2-associated binder (Gab) family of scaffolding adaptor proteins coordinate signaling cascades downstream of growth factor and cytokine receptors. In the heart, among EGF family members, neuregulin-1β (NRG-1β, a paracrine factor produced from endothelium) induced remarkable tyrosine phosphorylation of Gab1 and Gab2 via erythroblastic leukemia viral oncogene (ErbB) receptors. We examined the role of Gab family proteins in NRG-1β/ErbB-mediated signal in the heart by creating cardiomyocyte-specific Gab1/Gab2 double knockout mice (DKO mice). Although DKO mice were viable, they exhibited marked ventricular dilatation and reduced contractility with aging. DKO mice showed high mortality after birth because of heart failure. In addition, we noticed remarkable endocardial fibroelastosis and increase of abnormally dilated vessels in the ventricles of DKO mice. NRG-1β induced activation of both ERK and AKT in the hearts of control mice but not in those of DKO mice. Using DNA microarray analysis, we found that stimulation with NRG-1β upregulated expression of an endothelium-stabilizing factor, angiopoietin 1, in the hearts of control mice but not in those of DKO mice, which accounted for the pathological abnormalities in the DKO hearts. Taken together, our observations indicated that in the NRG-1β/ErbB signaling, Gab1 and Gab2 of the myocardium are essential for both maintenance of myocardial function and stabilization of cardiac capillary and endocardial endothelium in the postnatal heart.

Original languageEnglish
Pages (from-to)1771-1781
Number of pages11
JournalJournal of Clinical Investigation
Volume117
Issue number7
DOIs
Publication statusPublished - Jul 2 2007
Externally publishedYes

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Neuregulin-1
Knockout Mice
Maintenance
Proteins
Endothelium
Endocardial Fibroelastosis
Neuregulins
Angiopoietin-1
Cytokine Receptors
Growth Factor Receptors
Vascular Endothelium
Microarray Analysis
Oligonucleotide Array Sequence Analysis
Oncogenes
Epidermal Growth Factor
Cardiac Myocytes
Tyrosine
Dilatation
Myocardium
Leukemia

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling. / Nakaoka, Yoshikazu; Nishida, Keigo; Narimatsu, Masahiro; Kamiya, Atsunori; Minami, Takashi; Sawa, Hirofumi; Okawa, Katsuya; Fujio, Yasushi; Koyama, Tatsuya; Maeda, Makiko; Sone, Manami; Yamasaki, Satoru; Arai, Yuji; Gou, Young Koh; Kodama, Tatsuhiko; Hirota, Hisao; Otsu, Kinya; Hirano, Toshio; Mochizuki, Naoki.

In: Journal of Clinical Investigation, Vol. 117, No. 7, 02.07.2007, p. 1771-1781.

Research output: Contribution to journalArticle

Nakaoka, Y, Nishida, K, Narimatsu, M, Kamiya, A, Minami, T, Sawa, H, Okawa, K, Fujio, Y, Koyama, T, Maeda, M, Sone, M, Yamasaki, S, Arai, Y, Gou, YK, Kodama, T, Hirota, H, Otsu, K, Hirano, T & Mochizuki, N 2007, 'Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling', Journal of Clinical Investigation, vol. 117, no. 7, pp. 1771-1781. https://doi.org/10.1172/JCI30651
Nakaoka, Yoshikazu ; Nishida, Keigo ; Narimatsu, Masahiro ; Kamiya, Atsunori ; Minami, Takashi ; Sawa, Hirofumi ; Okawa, Katsuya ; Fujio, Yasushi ; Koyama, Tatsuya ; Maeda, Makiko ; Sone, Manami ; Yamasaki, Satoru ; Arai, Yuji ; Gou, Young Koh ; Kodama, Tatsuhiko ; Hirota, Hisao ; Otsu, Kinya ; Hirano, Toshio ; Mochizuki, Naoki. / Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 7. pp. 1771-1781.
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AU - Nakaoka, Yoshikazu

AU - Nishida, Keigo

AU - Narimatsu, Masahiro

AU - Kamiya, Atsunori

AU - Minami, Takashi

AU - Sawa, Hirofumi

AU - Okawa, Katsuya

AU - Fujio, Yasushi

AU - Koyama, Tatsuya

AU - Maeda, Makiko

AU - Sone, Manami

AU - Yamasaki, Satoru

AU - Arai, Yuji

AU - Gou, Young Koh

AU - Kodama, Tatsuhiko

AU - Hirota, Hisao

AU - Otsu, Kinya

AU - Hirano, Toshio

AU - Mochizuki, Naoki

PY - 2007/7/2

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N2 - Grb2-associated binder (Gab) family of scaffolding adaptor proteins coordinate signaling cascades downstream of growth factor and cytokine receptors. In the heart, among EGF family members, neuregulin-1β (NRG-1β, a paracrine factor produced from endothelium) induced remarkable tyrosine phosphorylation of Gab1 and Gab2 via erythroblastic leukemia viral oncogene (ErbB) receptors. We examined the role of Gab family proteins in NRG-1β/ErbB-mediated signal in the heart by creating cardiomyocyte-specific Gab1/Gab2 double knockout mice (DKO mice). Although DKO mice were viable, they exhibited marked ventricular dilatation and reduced contractility with aging. DKO mice showed high mortality after birth because of heart failure. In addition, we noticed remarkable endocardial fibroelastosis and increase of abnormally dilated vessels in the ventricles of DKO mice. NRG-1β induced activation of both ERK and AKT in the hearts of control mice but not in those of DKO mice. Using DNA microarray analysis, we found that stimulation with NRG-1β upregulated expression of an endothelium-stabilizing factor, angiopoietin 1, in the hearts of control mice but not in those of DKO mice, which accounted for the pathological abnormalities in the DKO hearts. Taken together, our observations indicated that in the NRG-1β/ErbB signaling, Gab1 and Gab2 of the myocardium are essential for both maintenance of myocardial function and stabilization of cardiac capillary and endocardial endothelium in the postnatal heart.

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