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J. Biol. Chem., Vol. 280, Issue 25, 24175-24180, June 24, 2005

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ERBB4/HER4 Potentiates STAT5A Transcriptional Activity by Regulating Novel STAT5A Serine Phosphorylation Events^*

Diane E. Clark, Christopher C. Williams, Tamika T. Duplessis, Kimberly L. Moring, Amy R. Notwick¶, Weiwen Long||, William S. Lane**, Iwan Beuvink, Nancy E. Hynes, and Frank E. Jones

From the Departments of Biochemistry, ^¶Pathology, and ^||Structural and Cellular Biology, Tulane University Health Sciences Center, Tulane Cancer Center, New Orleans, Louisiana 70112-2669, ^**Harvard Microchemistry and Proteomics Analysis Facility, Harvard University, Cambridge, Massachusetts 02138, and the Friedrich Miescher Institute, P. O. Box 2543, CH-4002 Basel, Switzerland

The epidermal growth factor receptor family member ERBB4 is required for mammary gland development and lactation. ERBB4 activities in the breast are mediated through the signal transducer and activator of transcription (STAT) family member STAT5A, and ERBB4 directly activates STAT5A, in part, through phosphorylation of STAT5A at the regulatory Tyr-694. Here we show that STAT5A regulation by ERBB4 is also mediated through STAT5A serine phosphorylation. Using a reverse-phase high performance liquid chromatography tandem mass spectrometry analysis of proteolytically digested STAT5A coexpressed with ERBB4, we identified STAT5A serine phosphorylations at the previously described Ser-779 and at the novel Ser-127/Ser-128. Immunohistochemistry of wild-type and ERBB4-null mammary glands at late pregnancy showed that ERBB4 expression was required for STAT5A phosphorylation at Ser-779. Independent serine-to-alanine residue substitutions in full-length STAT5A revealed that although STAT5A Ser-779 phosphorylation was dispensable for phosphorylation of STAT5A at Tyr-694 and subsequent DNA binding, Ser-779 was required to stabilize an interaction with ERBB4 and mediate ERBB4-induced STAT5A stimulation of gene expression. STAT5A Ser-127/Ser-128, on the other hand, was required for ERBB4-induced phosphorylation of Tyr-694, whereas Ser-779 and as yet unidentified tyrosine residues were phosphorylated in the absence of Ser-127/Ser-128. In addition, STAT5A S127A/S128A remained associated with ERBB4 but failed to bind DNA or activate transcription in response to ERBB4 coexpression. Our studies demonstrate that phosphorylation of STAT5A at Ser-127/Ser-128 and Ser-779 are obligatory events regulating ERBB4-mediated activation of STAT5A.

Received for publication, December 14, 2004 , and in revised form, March 28, 2005.

^* This work was supported by National Cancer Institute/National Institutes of Health Grants RO1CA95783 and RO1CA96717 (to F. E. J.), National Cancer Institute/National Institutes of Health Research Supplement for Underrepresented Minorities (to C. C. W.), and funds generously supplied through the National Cancer Coalition and the Tulane Cancer Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at www.jbc.org) contains Supplementary Fig. S1, featuring a mass spectrometry analysis of STAT5A phosphopeptides.

These authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Biochemistry, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112-2669. Tel.: 504-988-6585; Fax: 504-988-1687; E-mail, fjones{at}tulane.edu.

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