Constitutive activation of the prolactin receptor results in the induction of growth factor-independent proliferation and constitutive activation of signaling molecules

被引:31
作者
Lee, RCH
Walters, JA
Reyland, ME
Anderson, SM
机构
[1] Univ Colorado, Hlth Sci Ctr, Sch Med, Dept Pathol, Denver, CO 80262 USA
[2] Univ Colorado, Hlth Sci Ctr, Sch Dent, Dept Basic Sci & Oral Biol, Denver, CO 80262 USA
关键词
D O I
10.1074/jbc.274.15.10024
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The ability to induce the oncogenic activation of the human prolactin receptor (PRLR) was examined by deleting 178 amino acids of the extracellular ligand-binding domain. Expression of this deletion mutant in the interleukin-3 (IL-3)-dependent murine myeloid cell line 32Dc13 resulted in the induction of growth factor-independent proliferation. Parental 32Dc13 cells proliferated only in the presence of exogenous murine IL-3 (mIL-3), while 32Dc13 cells transfected with the long form of the human PRLR were able to proliferate in response to mIL-3, ovine prolactin, or human PRL, Cells expressing the Delta 178 deletion mutant contained numerous phosphotyrosine-containing proteins in the absence of stimulation with either mIL-3 or ovine prolactin, Growth factor stimulation increased the number of proteins phosphorylated and the intensity of phosphorylation, These proteins included constitutively phosphorylated Janus kinase 2, signal transducer and activator of transcription 5, and SHC. Activated extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) were observed in unstimulated 32Dc13 cells expressing the Delta 178 mutant. Likewise, transfection of Nb2 cells with the Delta 178 deletion mutant induced growth factor-independent proliferation and constitutive activation of Janus kinase 2, ERK1, and ERK2, In addition to the induction of a growth factor-independent state, the expression of the Delta 178 deletion mutant also suppressed the apoptosis that occurs when 32Dc13 cells are cultured in the absence of growth factors such as IL-3, These data suggest that the constitutive activation of the PRLR can be achieved by deletion of the ligand binding domain and that this mutation leads to the oncogenic activation of the receptor as determined by the ability of the receptor to induce growth factor-independent proliferation of factor-dependent hematopoietic cells.
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页码:10024 / 10034
页数:11
相关论文
共 66 条
[1]   Activation of phosphatidylinositol 3-kinase by prolactin in Nb2 cells [J].
AlSakkaf, KA ;
Dobson, PRM ;
Brown, BL .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1996, 221 (03) :779-784
[2]  
ANDERSON SM, 1995, J IMMUNOL, V155, P1660
[3]   Phosphorylation of Cbl following stimulation with interleukin-3 and its association with Grb2, Fyn, and phosphatidylinositol 3-kinase [J].
Anderson, SM ;
Burton, EA ;
Koch, BL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (02) :739-745
[4]  
ANDERSON SM, 1990, ONCOGENE, V5, P317
[5]  
ASKEW DS, 1991, ONCOGENE, V6, P1915
[6]   MULTIPLE INDEPENDENT ACTIVATIONS OF THE NEU ONCOGENE BY A POINT MUTATION ALTERING THE TRANSMEMBRANE DOMAIN OF P185 [J].
BARGMANN, CI ;
HUNG, MC ;
WEINBERG, RA .
CELL, 1986, 45 (05) :649-657
[7]   ONCOGENIC ACTIVATION OF THE NEU-ENCODED RECEPTOR PROTEIN BY POINT MUTATION AND DELETION [J].
BARGMANN, CI ;
WEINBERG, RA .
EMBO JOURNAL, 1988, 7 (07) :2043-2052
[8]  
Berlanga JJ, 1997, J BIOL CHEM, V272, P2050
[9]  
BISWAS R, 1987, CANCER RES, V47, P3509
[10]   Prolactin (PRL) and its receptor: Actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice [J].
Bole-Feysot, C ;
Goffin, V ;
Edery, M ;
Binart, N ;
Kelly, PA .
ENDOCRINE REVIEWS, 1998, 19 (03) :225-268