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Volume 272, Number 42, Issue of October 17, 1997 pp. 26761-26768
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

A Novel Juxtamembrane Domain Isoform of HER4/ErbB4
ISOFORM-SPECIFIC TISSUE DISTRIBUTION AND DIFFERENTIAL PROCESSING IN RESPONSE TO PHORBOL ESTER

(Received for publication, July 3, 1997)

Klaus Elenius , Gabriel Corfas ^¶ , Subroto Paul , Caroline J. Choi , Carlos Rio ^¶ , Gregory D. Plowman ^** and Michael Klagsbrun

From the  Departments of Surgery and Pathology and the ^¶ Division of Neuroscience and Department of Neurology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115 and ^** Sugen Inc., Redwood City, California 94063

Human epidermal growth factor receptor 4 (HER4) is a member of the epidermal growth factor (EGF) receptor subfamily of receptor tyrosine kinases that is activated by neuregulins (NRG), betacellulin (BTC), and heparin-binding EGF-like growth factor. Sequencing of full-length human HER4 cDNAs revealed the existence of two HER4 isoforms that differed by insertion of either 23 or 13 alternative amino acids in the extracellular juxtamembrane (JM) region. The 23-amino acid form (HER4 JM-a) and the 13-amino acid form (HER4 JM-b) were expressed in a tissue-specific manner, as demonstrated by reverse transcriptase-polymerase chain reaction analysis of mouse and human tissues. Both isoforms were expressed in neural tissues such as cerebellum, whereas kidney expressed HER4 JM-a only and heart HER4 JM-b only. In situ hybridization using specific oligonucleotides demonstrated transcription of both JM-a and JM-b isoforms in the mouse cerebellum. Tyrosine phosphorylation analysis indicated that both receptor isoforms were activated to the same extent by NRG-1 and BTC, and to a lesser extent by NRG-1 and heparin-binding EGF-like growth factor. A functional difference was found, however, in response to phorbol ester treatment. Stimulation of cells with phorbol ester resulted in a loss of ¹²⁵I-NRG-1 binding and in a reduction of total cell-associated HER4 protein in HER4 JM-a transfectants but not in HER4 JM-b transfectants. It was concluded that novel alternatively spliced isoforms of HER4 exist, that they are distributed differentially in vivo in mouse and human tissues, that they are both activated by HER4 ligands, and that they may represent cleavable and noncleavable forms of HER4.

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