K. Elenius et al., A NOVEL JUXTAMEMBRANE DOMAIN ISOFORM OF HER4 ERBB4 - ISOFORM-SPECIFICTISSUE DISTRIBUTION AND DIFFERENTIAL PROCESSING IN RESPONSE TO PHORBOL ESTER/, The Journal of biological chemistry, 272(42), 1997, pp. 26761-26768
Human epidermal growth factor receptor 4 (HER4) is a member of the epi
dermal growth factor (EGF) receptor subfamily of receptor tyrosine kin
ases that is activated by neuregulins (NRG), betacellulin (ETC), and h
eparin-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 extrace
llular juxtamembrane (JM) region, The 23-amino acid form (HERC JM-a) a
nd the 13-amino acid form (HER4 JM-b) were expressed in a tissue-speci
fic manner, as demonstrated by reverse transcriptase-polymerase chain
reaction analysis of mouse and human tissues. Both isoforms were expre
ssed in neural tissues such as cerebellum, whereas kidney expressed HE
R4 JM-a only and heart HER4 JM-b only, In situ hybridization using spe
cific oligonucleotides demonstrated transcription of both JM-a and JM-
b isoforms in the mouse cerebellum, Tyro sine phosphorylation analysis
indicated that both receptor isoforms were activated to the same exte
nt by NRG-beta 1 and ETC, and to a lesser extent by NRG-alpha 1 and he
parin-binding EGF-like growth factor. A functional difference was foun
d, however, in response 60 phorbol ester treatment, Stimulation of cel
ls with phorbol ester resulted in a loss of I-125-NRG-beta 1 binding a
nd in a reduction of total cell-associated HER4 protein in HER4 JM-a t
ransfectants but not in HER4 JM-b transfectants. It was concluded that
novel alternatively spliced isoforms of HER4 exist, that they are dis
tributed differentially in vivo in mouse and human tissues, that they
are both activated by HER4 ligands, and that they may represent cleava
ble and noncleavable forms of HER4.