Role of mitogen-activated protein kinase kinase in regulation of the epidermal growth factor receptor by protein kinase C

被引:48
作者
Morrison, P
Saltiel, AR
Rosner, MR
机构
[1] UNIV CHICAGO,BEN MAY INST,CHICAGO,IL 60637
[2] UNIV CHICAGO,DEPT PHARMACOL & PHYSIOL SCI,CHICAGO,IL 60637
[3] UNIV CHICAGO,DEPT MOLEC GENET & CELL BIOL,CHICAGO,IL 60637
[4] WARNER LAMBERT PARKE DAVIS,DIV PHARMACEUT RES,DEPT SIGNAL TRANSDUCT,ANN ARBOR,MI 48105
关键词
D O I
10.1074/jbc.271.22.12891
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 epidermal growth factor receptor (EGFR) is regulated by at least two mechanisms involving protein kinase C (PKC), inhibition of EGF binding and inhibition of EGF-stimulated tyrosine kinase activity. In this study we investigated whether mitogen-activated protein kinase (MAPK) mediates the inhibitory effects of PKC on EGFR binding or kinase activity by pretreating NIH3T3 and Chinese hamster ovary cells expressing the EGFR with PD98059, an inhibitor of MAPK/extracellular signal-regulated kinase kinase (MEK). We also determined whether substitution of cysteine for threonine at residue 669, the site of MAPK phosphorylation of the EGFR, alters the inhibition of kinase activity by PKC. The results indicate that 1) PKC down-regulates EGFR tyrosine kinase activity by an MEK-dependent mechanism presumably involving MAPK; 2) the inhibition by PKC is not a direct result of phosphorylation of the EGFR by PKC or MAPK; 3) activation of MAPK is not sufficient to regulate EGFR kinase activity; and 4) PKC-mediated down-regulation of EGF binding and EGFR kinase activity occur by different mechanisms. These data are consistent with a model for regulation of the EGFR by other receptors whereby their activation of PKC, in conjunction with MAPK, results in the phosphorylation of a protein(s) that modulates EGFR kinase activity.
引用
收藏
页码:12891 / 12896
页数:6
相关论文
共 28 条
[1]   PD-098059 IS A SPECIFIC INHIBITOR OF THE ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASE KINASE IN-VITRO AND IN-VIVO [J].
ALESSI, DR ;
CUENDA, A ;
COHEN, P ;
DUDLEY, DT ;
SALTIEL, AR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (46) :27489-27494
[2]  
CASTAGNINO P, 1995, ONCOGENE, V10, P723
[3]  
CHAO TSO, 1992, J BIOL CHEM, V267, P19876
[4]  
COCHET C, 1991, J BIOL CHEM, V266, P637
[5]  
COUNTAWAY JL, 1990, J BIOL CHEM, V265, P3407
[6]  
DECKER SJ, 1990, J BIOL CHEM, V265, P7009
[7]  
DOWNWARD J, 1985, J BIOL CHEM, V260, P14358
[8]   A SYNTHETIC INHIBITOR OF THE MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE [J].
DUDLEY, DT ;
PANG, L ;
DECKER, SJ ;
BRIDGES, AJ ;
SALTIEL, AR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (17) :7686-7689
[9]   KINETICS OF BINDING, ENDOCYTOSIS, AND RECYCLING OF EGF RECEPTOR MUTANTS [J].
FELDER, S ;
LAVIN, J ;
ULLRICH, A ;
SCHLESSINGER, J .
JOURNAL OF CELL BIOLOGY, 1992, 117 (01) :203-212
[10]   A MUTATION IN THE EPIDERMAL GROWTH-FACTOR RECEPTOR IN WAVED-2 MICE HAS A PROFOUND EFFECT ON RECEPTOR BIOCHEMISTRY THAT RESULTS IN IMPAIRED LACTATION [J].
FOWLER, KJ ;
WALKER, F ;
ALEXANDER, W ;
HIBBS, ML ;
NICE, EC ;
BOHMER, RM ;
MANN, GB ;
THUMWOOD, C ;
MAGLITTO, R ;
DANKS, JA ;
CHETTY, R ;
BURGESS, AW ;
DUNN, AR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (05) :1465-1469