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Molecular and Cellular Biology, February 2009, p. 892-906, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.00595-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The E3 Ubiquitin Ligase WWP1 Selectively Targets HER4 and Its Proteolytically Derived Signaling Isoforms for Degradation{triangledown}

Shu-Mang Feng,1 Rebecca S. Muraoka-Cook,1,2 Debra Hunter,1 Melissa A. Sandahl,1 Laura S. Caskey,1 Keiji Miyazawa,4 Azeddine Atfi,5 and H. Shelton Earp III1,3*

UNC Lineberger Comprehensive Cancer Center,1 Department of Genetics,2 Department of Medicine and Pharmacology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina 27599,3 Department of Molecular Pathology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan,4 INSERM U 482, Hôpital St-Antoine, Paris, France5

Received 11 April 2008/ Returned for modification 28 May 2008/ Accepted 19 November 2008

In general, epidermal growth factor receptor family members stimulate cell proliferation. In contrast, at least one HER4 isoform, JM-a/Cyt1, inhibits cell growth after undergoing a two-step proteolytic cleavage that first produces a membrane-anchored 80-kDa fragment (m80HER4) and subsequently liberates a soluble 80-kDa fragment, s80HER4. Here we report that s80HER4 Cyt1 action increased the expression of WWP1 (for WW domain-containing protein 1), an E3 ubiquitin ligase, but not other members of the Nedd4 E3 ligase family. The HER4 Cyt1 isoform contains three proline-rich tyrosine (PY) WW binding motifs, while Cyt2 has only two. WWP1 binds to all three Cyt1 PY motifs; the interaction with PY2 found exclusively in Cyt1 was strongest. WWP1 ubiquitinated and caused the degradation of HER4 but not of EGFR, HER2, or HER3. The HER4-WWP1 interaction also accelerated WWP1 degradation. Membrane HER4 (full length and m80HER4, the product of the first proteolytic cleavage) were the preferred targets of WWP1, correlating with the membrane localization of WWP1. Conversely s80HER4, a poorer WWP1 substrate, was found in the cell nucleus, while WWP1 was not. Deletion of the C2 membrane association domain of WWP1 allowed more efficient s80HER4 degradation, suggesting that WWP1 is normally part of a membrane complex that regulates HER4 membrane species levels, with a predilection for the growth-inhibitory Cyt1 isoform. Finally, WWP1 expression diminished HER4 biologic activity in MCF-7 cells. We previously showed that nuclear s80HER4 is ubiquitinated and degraded by the anaphase-promoting complex, suggesting that HER4 ubiquitination within specific cellular compartments helps regulate the unique HER4 signaling capabilities.

* Corresponding author. Mailing address: UNC Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, 102 Mason Farm Road, Chapel Hill, NC 27599. Phone: (919) 966-2335. Fax: (919) 966-3015. E-mail: hse{at}med.unc.edu

{triangledown} Published ahead of print on 1 December 2008.

Molecular and Cellular Biology, February 2009, p. 892-906, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.00595-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Muraoka-Cook, R. S., Sandahl, M. A., Strunk, K. E., Miraglia, L. C., Husted, C., Hunter, D. M., Elenius, K., Chodosh, L. A., Earp, H. S. III (2009). ErbB4 Splice Variants Cyt1 and Cyt2 Differ by 16 Amino Acids and Exert Opposing Effects on the Mammary Epithelium In Vivo. Mol. Cell. Biol. 29: 4935-4948 [Abstract] [Full Text]  


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