Transforming growth factor β induces clustering of HER2 and integrins by activating Src-focal adhesion kinase and receptor association to the cytoskeleton

Shizhen Emily Wang, Bin Xiang, Roy Zent, Vito Quaranta, Ambra Pozzi, Carlos L. Arteaga

Research output: Contribution to journalArticle

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Abstract

It has been proposed that cross talk between integrin and growth factor receptor signaling such as ErbB2 (HER2) is required for activation of downstream effectors and ErbB2-mediated mammary tumorigenes is. Here we show that transforming growth factor β (TGF-β) induced focal adhesion kinase (FAK)-dependent clustering of HER2 and integrins α6, β1, and β4 in HER2-overexpressing mammary epithelial cells without altering the total and surface levels of HER2 receptors. This effect was mediated by ligand-induced epidermal growth factor receptor (EGFR) activation and the subsequent phosphorylation of Src and FAK. We have previously reported that TGF-β up-regulates EGFR ligand shedding through a mechanism involving the phosphorylation of tumor necrosis factor-α-converting enzyme (TACE/ADAM17). Knockdown of TACE, FAK, or integrin α6 by siRNA or inhibition of EGFR or Src by specific inhibitors abrogated TGF-β-induced receptor clustering and signaling to phosphatidylinositol 3-kinase-Akt. Finally, inhibition of Src-FAK reversed TGF-β-induced resistance to the therapeutic HER2 inhibitor trastuzumab in HER2-overexpressing breast cancer cells. Taken together, these data suggest that, by activating Src-FAK, TGF-β integrates ErbB receptor and integrin signaling to induce cell migration and survival during breast cancer progression.

Original languageEnglish (US)
Pages (from-to)475-482
Number of pages8
JournalCancer Research
Volume69
Issue number2
DOIs
StatePublished - Jan 15 2009

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Focal Adhesion Protein-Tyrosine Kinases
Transforming Growth Factors
Cytoskeleton
Integrins
Cluster Analysis
Epidermal Growth Factor Receptor
Growth Factor Receptors
Breast
Phosphorylation
Phosphatidylinositol 3-Kinase
Breast Neoplasms
Ligands
Small Interfering RNA
Cell Movement
Cell Survival
Up-Regulation
Tumor Necrosis Factor-alpha
Epithelial Cells
adhesion receptor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Transforming growth factor β induces clustering of HER2 and integrins by activating Src-focal adhesion kinase and receptor association to the cytoskeleton. / Wang, Shizhen Emily; Xiang, Bin; Zent, Roy; Quaranta, Vito; Pozzi, Ambra; Arteaga, Carlos L.

In: Cancer Research, Vol. 69, No. 2, 15.01.2009, p. 475-482.

Research output: Contribution to journalArticle

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AU - Arteaga, Carlos L.

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