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J Biol Chem, Vol. 274, Issue 50, 35461-35468, December 10, 1999
From the Department of Pathology and Laboratory Medicine,
University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania 19104
Prolactin-dependent signaling occurs
as the result of ligand-induced dimerization of the prolactin receptor
(PRLr). While three PRLr isoforms have been characterized in the rat,
studies have suggested the existence of several human isoforms in
breast carcinoma species and normal tissues. Reverse transcription
polymerase chain reaction was performed on mRNA isolated from the
breast carcinoma cell line T47D, revealing two predominant receptor
isoforms: the previously described long PRLr and a novel human
intermediate PRLr. The nucleotide sequence of the intermediate isoform
was found to be identical to the long isoform except for a 573-base pair deletion occurring at a consensus splice site, resulting in a
frameshift and truncated intracytoplasmic domain. Scatchard analysis of
the intermediate PRLr revealed an affinity for PRL comparable with the
long PRLr. While Ba/F3 transfectants expressing the long PRLr
proliferated in response to PRL, intermediate PRLr transfectants
exhibited modest incorporation of [3H]thymidine.
Significantly, however, both the long and intermediate PRLr were
equivalent in their inhibition of apoptosis of the Ba/F3 transfectants
after PRL treatment. The activation of proximal signaling molecules
also differed between isoforms. Upon ligand binding, Jak2 and Fyn were
activated in CHO-K1 cells transiently transfected with the long PRLr.
In contrast, the intermediate PRLr transfectants showed equivalent
levels of Jak2 activation but only minimal activation of Fyn. Last,
Northern analysis revealed variable tissue expression of intermediate
PRLr transcript that differed from that of the long PRLr. Taken
together, differences in signaling and tissue expression suggest that
the human intermediate PRLr differs from the long PRLr in physiological function.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF166329.
Functional Characterization of the Intermediate Isoform of the
Human Prolactin Receptor*
*
This study was supported in part by the National Institutes
of Health grants 2R01CA69294 (to C. V. C.) and 1F32DK09727 (to J. B. K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Pathology & Laboratory Medicine, University of Pennsylvania Medical Center, 509 Stellar-Chance Labs, 422 Curie Blvd., Philadelphia, PA 19104. E-mail:
clevengc@mail.med.upenn.edu.
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