DISTINCT CYTOPLASMIC REGIONS OF THE GROWTH-HORMONE RECEPTOR ARE REQUIRED FOR ACTIVATION OF JAK2, MITOGEN-ACTIVATED PROTEIN-KINASE, AND TRANSCRIPTION

被引:123
作者
SOTIROPOULOS, A [1 ]
PERROTAPPLANAT, M [1 ]
DINERSTEIN, H [1 ]
PALLIER, A [1 ]
POSTELVINAY, MC [1 ]
FINIDORI, J [1 ]
KELLY, PA [1 ]
机构
[1] FAC MED NECKER ENFANTS MALAD, INSERM, U344, F-75730 PARIS, FRANCE
关键词
D O I
10.1210/en.135.4.1292
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The GH receptor (GHR) is a member of the cytokine/hematopoietic growth factor family, and protein tyrosine phosphorylation has been implicated in the signaling cascade of these receptors. It was recently shown that the tyrosine kinase JAK2 is associated with the GHR. GH induces the activation of JAK2, which phosphorylates itself and the receptor. Mitogen-activated protein (MAP) kinase activation and transcriptional stimulation of specific genes, such as Spi 2.1, have also been reported to be induced by GH. To identify functionally important regions in the cytoplasmic domain of the GHR, we compared the actions of the wild-type receptor, two truncated mutants, and one internal deletion mutant (similar to the intermediate Nb2 form of the PRL receptor) in transfectants of the Chinese hamster ovary cell line. A region of 46 amino acids adjacent to the membrane was found to be sufficient for activation of both JAK2 and MAP kinases. This region contains a proline-rich sequence (box 1) conserved in the cytokine receptor family that is important for signal transduction. For transcriptional activity, the C-terminal region of the GHR is required, and we found that the last 80 terminal residues contain sequences allowing activation of the Spi 2.1 promoter. Tyrosine phosphorylation of the receptor also requires the C-terminal portion of the GHR cytoplasmic domain, and we found that GHR tyrosine phosphorylation appears to be linked to activation of the Spi 2.1 transcription pathway. Thus, the GHR could be composed of at least 2 functional regions: the 46 proximal amino acids required for activation of JAK2 and sufficient to stimulate the MAP kinase pathway, and an additional carboxy-terminal region necessary for transcriptional activation.
引用
收藏
页码:1292 / 1298
页数:7
相关论文
共 30 条
[1]  
ALI S, 1991, J BIOL CHEM, V266, P20110
[2]   THE NB2 FORM OF PROLACTIN RECEPTOR IS ABLE TO ACTIVATE A MILK PROTEIN GENE PROMOTER [J].
ALI, S ;
EDERY, M ;
PELLEGRINI, I ;
LESUEUR, L ;
PALY, J ;
DJIANE, J ;
KELLY, PA .
MOLECULAR ENDOCRINOLOGY, 1992, 6 (08) :1242-1248
[3]   IDENTIFICATION OF JAK2 AS A GROWTH-HORMONE RECEPTOR-ASSOCIATED TYROSINE KINASE [J].
ARGETSINGER, LS ;
CAMPBELL, GS ;
YANG, XN ;
WITTHUHN, BA ;
SILVENNOINEN, O ;
IHLE, JN ;
CARTERSU, C .
CELL, 1993, 74 (02) :237-244
[4]   MULTIPLE REGIONS WITHIN THE CYTOPLASMIC DOMAINS OF THE LEUKEMIA INHIBITORY FACTOR-RECEPTOR AND GP130 COOPERATE IN SIGNAL-TRANSDUCTION IN HEPATIC AND NEURONAL CELLS [J].
BAUMANN, H ;
SYMES, AJ ;
COMEAU, MR ;
MORELLA, KK ;
WANG, YP ;
FRIEND, D ;
ZIEGLER, SF ;
FINK, JS ;
GEARING, DP .
MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (01) :138-146
[6]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[7]  
CAMPBELL GS, 1992, J BIOL CHEM, V267, P6074
[8]  
CAMPBELL GS, 1993, J BIOL CHEM, V268, P7427
[9]  
CLARKLEWIS I, 1991, J BIOL CHEM, V266, P15180
[10]  
COLOSI P, 1993, J BIOL CHEM, V268, P12617