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Muc4/sialomucin complex, the intramembrane ErbB2 ligand, induces specific phosphorylation of ErbB2 and enhances expression of p27kip, but does not activate mitogen-activated kinase or protein kinaseB/Akt pathways

Oncogene volume 21, pages 7524–7532 (2002)Cite this article

Abstract

Muc4/sialomucin complex (SMC) is a multifunctional glycoprotein complex which can repress apoptosis in transfected tumor cells. Its transmembrane subunit acts as an intramembrane ligand for the receptor tyrosine kinase ErbB2 to induce the phosphorylation of ErbB2 and, by acting synergistically with the ErbB3 ligand neuregulin, can potentiate the phosphorylation of ErbB2 and ErbB3. In the present study we show that Muc4/SMC alone robustly induces the phosphorylation of ErbB2 to enhance the tyrosine phosphate epitope (Tyr1248) recognized by anti-phospho-ErbB2. Although this tyrosine phosphorylation has been implicated in cell transformation, it does not activate any of the three mitogen-activated protein kinases (MAPKs) or protein kinase B/Akt of the phosphatidyl inositol 3-kinase pathway. Instead, Muc4/SMC expression induces up-regulation of the cell cycle inhibitor p27kip, consistent with the expression of Muc4/SMC in differentiated, rather than proliferative, epithelial cells. Interestingly, a combination of Muc4/SMC and neuregulin down-regulate p27kip and activate protein kinase B/Akt. These observations suggest that Muc4/SMC acts as a regulator of differentiation by inducing a limited phosphorylation of ErbB2 and a modulator of proliferation when acting synergistically with neuregulin to induce a more extensive phosphorylation on both ErbB2 and ErbB3.

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Acknowledgements

We thank Jin Zhang for help in preparing the manuscript. This research was supported in part by Grant CA74072 from the National Institutes of Health and by the Sylvester Comprehensive Cancer Center of the University of Miami, USA.

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Author notes

  1. Scott Jepson and Masanobu Komatsu: Scott Jepson and Masanobu Komatsu contributed equally to this study

Authors and Affiliations

  1. Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, 33101, Florida, FL, USA

    Scott Jepson, Masanobu Komatsu, Maria E Arango, Daming Huang & Kermit L Carraway

  2. Department of Biochemistry, University of Miami School of Medicine, Miami, 33101, Florida, FL, USA

    Bushra Haq & Coralie A Carothers Carraway

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  1. Scott Jepson
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  2. Masanobu Komatsu
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Correspondence to Kermit L Carraway.

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Jepson, S., Komatsu, M., Haq, B. et al. Muc4/sialomucin complex, the intramembrane ErbB2 ligand, induces specific phosphorylation of ErbB2 and enhances expression of p27kip, but does not activate mitogen-activated kinase or protein kinaseB/Akt pathways. Oncogene 21, 7524–7532 (2002). https://doi.org/10.1038/sj.onc.1205970

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