ErbB2 expression increases the spectrum and potency of ligand-mediated signal transduction through ErbB4

被引:87
作者
Wang, LM
Kuo, A
Alimandi, M
Veri, MC
Lee, CC
Kapoor, V
Ellmore, N
Chen, XH
Pierce, JH
机构
[1] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA
[2] Univ La Sapienza, Dipartimento Med Sperimentale, I-00161 Rome, Italy
[3] Inst Tumori, Immunol Lab, Rome, Italy
关键词
D O I
10.1073/pnas.95.12.6809
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Interleukin 3-dependent murine 32D cells do not detectably express members of the ErbB receptor family and do not proliferate in response to known ligands for these receptors, 32D transfectants were generated expressing human ErbB4 alone (32D.E4) or with ErbB2 (32D.E2/E4), Epidermal growth factor (EGF), neuregulin 1-beta (NRG1-beta), betacellulin (BTC), transforming growth factor-alpha (TGF-alpha), heparin binding-EGF (HB-EGF), and amphiregulin were analyzed for their ability to mediate mitogenesis in these transfectants. 32D.E4 responded mitogenically to NRG1-beta and BTC. Surprisingly, EGF also induced significant DNA synthesis and TGF-alpha was negligibly mitogenic on 32D.E4 cells, whereas HB-EGF and amphiregulin were inactive, Although coexpression of ErbB2 with ErbB4 in 32D.E2/E4 cells did not significantly alter DNA synthesis in response to NRG1-beta or BTC, it greatly enhanced mitogenesis elicited by EGF and TGF-alpha and unmasked the ability of HB-EGF to induce proliferation. EGF-related ligands that exhibited potent mitogenic activity on 32D.E2/E4 cells at low concentrations induced adherence, morphological alterations, and up-regulation of the Mac-1 integrin and Fc gamma RII/III at higher concentrations. While I-125-EGF could be specifically crosslinked to both 32D.E4 and 32D.E2/E4 cells, its crosslinking capacity was greatly enhanced in the cotransfected cells. The ability of the various ligands to mediate proliferation and/or adhesion in the two transfectants correlated with their capacity to induce substrate tyrosine phosphorylation and to initiate and sustain activation of mitogen-activated protein kinase, We conclude that the ability of ErbB4 to mediate signal transduction through EGF-like ligands is broader than previously assumed and can be profoundly altered by the concomitant expression of ErbB2.
引用
收藏
页码:6809 / 6814
页数:6
相关论文
共 55 条
  • [1] Epidermal growth factor and betacellulin mediate signal transduction through co-expressed ErbB2 and ErbB3 receptors
    Alimandi, M
    Wang, LM
    Bottaro, D
    Lee, CC
    Kuo, A
    Frankel, M
    Fedi, P
    Tang, C
    Lippman, M
    Pierce, JH
    [J]. EMBO JOURNAL, 1997, 16 (18) : 5608 - 5617
  • [2] ALIMANDI M, 1995, ONCOGENE, V10, P1813
  • [3] The ErbB signaling network in embryogenesis and oncogenesis: Signal diversification through combinatorial ligand-receptor interactions
    Alroy, I
    Yarden, Y
    [J]. FEBS LETTERS, 1997, 410 (01) : 83 - 86
  • [4] BACUS SS, 1993, CANCER RES, V53, P5251
  • [5] BACUS SS, 1992, CANCER RES, V52, P2580
  • [6] THE STRUCTURAL BASIS FOR THE SPECIFICITY OF EPIDERMAL GROWTH-FACTOR AND HEREGULIN BINDING
    BARBACCI, EG
    GUARINO, BC
    STROH, JG
    SINGLETON, DH
    ROSNACK, KJ
    MOYER, JD
    ANDREWS, GC
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (16) : 9585 - 9589
  • [7] CARRAWAY KL, 1994, J BIOL CHEM, V269, P14303
  • [8] Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases
    Carraway, KL
    Weber, JL
    Unger, MJ
    Ledesma, J
    Yu, N
    Gassmann, M
    Lai, C
    [J]. NATURE, 1997, 387 (6632) : 512 - 516
  • [9] Ligands for ErbB-family receptors encoded by a neuregulin-like gene
    Chang, H
    Riese, DJ
    Gilbert, W
    Stern, DF
    McMahan, UJ
    [J]. NATURE, 1997, 387 (6632) : 509 - 512
  • [10] Cohen BM, 1996, J BIOL CHEM, V271, P4813