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Defective cleavage of membrane bound TGFα leads to enhanced activation of the EGF receptor in malignant cells

Oncogene volume 19, pages 1901–1914 (2000)Cite this article

Abstract

Transforming growth factor α (TGFα) is widely expressed in malignant as well as normal cells and is involved in regulating cell growth and differentiation. Although processing of TGFα has been extensively studied in normal cells, there is little information regarding TGFα cleavage in malignant cells. Therefore, we compared the processing of TGFα in two human colon carcinoma cell lines. We found that there was a defective cleavage pattern for the TGFα precursor resulting in retention of partially processed TGFα on the cell surface of both the HCT116a2αS3 and CBS4αS2 cell lines. This raised the possibility that signaling from the resulting defective cleavage species could differ from that of soluble TGFα. The membrane-associated TGFα induced higher phosphorylation of EGFR on the cell surface of adjacent cells than equivalent levels of mature TGFα. The interaction of membrane bound TGFα precursor with the EGFR caused a slower internalization of activated EGFR relative to the internalization of the soluble TGFα/EGFR complexes. In addition, the tethered TGFα was resistant to the ability of protein-tyrosine phosphatases (PTPs) to reduce EGFR tyrosine phosphorylation, also contributing to higher activation of EGFR. The enhanced activation of EGFR by the tethered form of TGFα was reflected by higher activation of Grb2, SHC and Erk downstream mediators of EGF receptor signaling. The higher activation of EGFR by membrane tethered TGFα indicates that defective TGFα processing provides a mechanism whereby malignant cells can obtain a growth advantage over normal cells.

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Abbreviations

TGFα:

transforming growth factor α

EGF:

epidermal growth factor

EGFR:

EGF receptor

TPA:

12-O-Tetra-decanoylphorbol 13-acetate

PTP:

protein-tyrosine phosphatase

PAO:

phenyl arsine oxide

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Acknowledgements

This work was supported by NIH grants CA34432 and CA54807.

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Authors and Affiliations

  1. Department of Surgery, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78284-7840, Texas, TX, USA

    Haisu Yang, Wenhui Li & Michael G Brattain

  2. Department of Biochemistry, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78284-7840, Texas, TX, USA

    Haisu Yang, Wenhui Li & Michael G Brattain

  3. Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, 43699, Ohio, OH, USA

    Dianhua Jiang, Jiurong Liang & Larry E Gentry

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  1. Haisu Yang
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Yang, H., Jiang, D., Li, W. et al. Defective cleavage of membrane bound TGFα leads to enhanced activation of the EGF receptor in malignant cells. Oncogene 19, 1901–1914 (2000). https://doi.org/10.1038/sj.onc.1203513

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