Regulation of the urokinase-type plasminogen activator gene by the oncogene Tpr-Met involves GRB2

被引:48
作者
Besser, D
Bardelli, A
Didichenko, S
Thelen, M
Comoglio, PM
Ponzetto, C
Nagamine, Y
机构
[1] FRIEDRICH MIESCHER INST,CH-4002 BASEL,SWITZERLAND
[2] UNIV TURIN,SCH MED,DEPT BIOMED SCI & ONCOL,I-10126 TURIN,ITALY
[3] UNIV BERN,THEODOR KOCHER INST,CH-3012 BERN,SWITZERLAND
[4] UNIV TURIN,SCH MED,CANC RES INST,I-10126 TURIN,ITALY
关键词
GRB2; hepatocyte growth factor; plasminogen activator; signal transduction; Tpr-Met;
D O I
10.1038/sj.onc.1200879
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 oncogene Tpr-Met is a constitutively active form of the hepatocyte growth factor/scatter factor (HGF/SF) receptor Met. It comprises the intracellular moiety of Met linked to the dimerization domain of the nuclear envelope protein Tpr, thus functioning as a constitutively activated Met, HGF/SF is responsible for various biological processes including angiogenesis and wound healing, in which secreted serine protease urokinase-type plasminogen activator (uPA) is implicated, The action of HGF/SF on cells is mediated by the autophosphorylation of Met on two carboxyterminal tyrosine Y(1349)VHVNATVY(1356)VNV. The two tyrosine provide docking sites for various effector molecules, suggesting that multiple signaling pathways are activated to exert biological effects of HGF/SF [Ponzetto et al., Cell (1994) 77: 261], We found that Tpr-Met efficiently activates the uPA gene via a SOS/Ras/extracellular signal regulated kinase (ERK)-dependent signaling pathway, Mutation of Y-1356, which abrogates GRB2 binding, reduced the induction to half of the control level, while mutation of Y-1349 showed little effect on uPA induction, suggesting an important but partly replaceable role for GRB2 in Met-dependent uPA gene induction, Mutation of both (YVHV)-V-1349 and (YVNV)-V-1356 into optimal PI 3-kinase sites resulted in a residual induction of about one quarter of the control level, suggesting a potential role for PI 3-kinase, Dose-response analysis of the Tpr-Met showed a biphasic curve, These results suggest that the interplay among different signaling molecules on the receptor is important for full induction of the pathway leading to the activation of the uPA gene.
引用
收藏
页码:705 / 711
页数:7
相关论文
共 54 条
  • [11] MOLECULAR-CLONING OF A NEW TRANSFORMING GENE FROM A CHEMICALLY TRANSFORMED HUMAN CELL-LINE
    COOPER, CS
    PARK, M
    BLAIR, DG
    TAINSKY, MA
    HUEBNER, K
    CROCE, CM
    VANDEWOUDE, GF
    [J]. NATURE, 1984, 311 (5981) : 29 - 33
  • [12] THE INHIBITION OF GLYCOGEN-SYNTHASE KINASE-3 BY INSULIN OR INSULIN-LIKE GROWTH-FACTOR-1 IN THE RAT SKELETAL-MUSCLE CELL-LINE-L6 IS BLOCKED BY WORTMANNIN, BUT NOT BY RAPAMYCIN - EVIDENCE THAT WORTMANNIN BLOCKS ACTIVATION OF THE MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY IN L6-CELLS BETWEEN RAS AND RAF
    CROSS, DAE
    ALESSI, DR
    VANDENHEEDE, JR
    MCDOWELL, HE
    HUNDAL, HS
    COHEN, P
    [J]. BIOCHEMICAL JOURNAL, 1994, 303 : 21 - 26
  • [13] PLASMINOGEN ACTIVATORS, TISSUE DEGRADATION, AND CANCER
    DANO, K
    ANDREASEN, PA
    GRONDAHLHANSEN, J
    KRISTENSEN, P
    NIELSEN, LS
    SKRIVER, L
    [J]. ADVANCES IN CANCER RESEARCH, 1985, 44 : 139 - 266
  • [14] DEGEN JL, 1985, J BIOL CHEM, V260, P2426
  • [15] INVOLVEMENT OF P21RAS IN ACTIVATION OF EXTRACELLULAR SIGNAL-REGULATED KINASE-2
    DEVRIESSMITS, AMM
    BURGERING, BMT
    LEEVERS, SJ
    MARSHALL, CJ
    BOS, JL
    [J]. NATURE, 1992, 357 (6379) : 602 - 604
  • [16] OVEREXPRESSION OF THE MET HGF RECEPTOR IN OVARIAN-CANCER
    DIRENZO, MF
    OLIVERO, M
    KATSAROS, D
    CREPALDI, T
    GAGLIA, P
    ZOLA, P
    SISMONDI, P
    COMOGLIO, PM
    [J]. INTERNATIONAL JOURNAL OF CANCER, 1994, 58 (05) : 658 - 662
  • [17] FERRACINI R, 1991, J BIOL CHEM, V266, P19558
  • [18] GHERARDI E, 1991, CANCER CELL-MON REV, V3, P227
  • [19] TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION OF UROKINASE-TYPE PLASMINOGEN-ACTIVATOR EXPRESSION IN ENDOTHELIAL-CELLS BY BASIC FIBROBLAST GROWTH-FACTOR
    GUALANDRIS, A
    PRESTA, M
    [J]. JOURNAL OF CELLULAR PHYSIOLOGY, 1995, 162 (03) : 400 - 409
  • [20] THE PROTEIN-KINASE FAMILY - CONSERVED FEATURES AND DEDUCED PHYLOGENY OF THE CATALYTIC DOMAINS
    HANKS, SK
    QUINN, AM
    HUNTER, T
    [J]. SCIENCE, 1988, 241 (4861) : 42 - 52