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Research ArticleCELLULAR AND MOLECULAR

Bradykinin B2 Receptor Activates Extracellular Signal-Regulated Protein Kinase in mIMCD-3 Cells via Epidermal Growth Factor Receptor Transactivation

Yurii V. Mukhin, Evgeny A. Garnovsky, Michael E. Ullian and Maria N. Garnovskaya
Journal of Pharmacology and Experimental Therapeutics March 2003, 304 (3) 968-977; DOI: https://doi.org/10.1124/jpet.102.043943
Yurii V. Mukhin
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Evgeny A. Garnovsky
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Michael E. Ullian
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Maria N. Garnovskaya
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Abstract

Bradykinin (BK) has been implicated in the regulation of renal function. Activation of extracellular signal-regulated protein kinase (ERK1/2) has been demonstrated in several models of toxic or proliferative renal injury. We studied activation of ERK1/2 by BK in a cell model of the most distal part of the nephron, inner medullary collecting duct (mIMCD-3) cells. Exposure of mIMCD-3 cells to BK (10−10–10−5 M) resulted in a concentration-dependent increase in tyrosine phosphorylation of ERK1/2, with maximal effect at 10−8 M BK. ERK1/2 activation by BK was observed as early as 1 min, peaked at 5 min, and was sustained at least for 1 h. The effect of BK was mediated by the B2receptor and was pertussis toxin-independent. Inhibition of phospholipase C, protein kinase C, or phosphatidylinositol 3-kinase did not alter ERK1/2 activation by BK. BK-induced ERK1/2 activation was Ca2+-calmodulin-independent but was sensitive to genistein, an inhibitor of tyrosine kinase(s). AG1478, a specific inhibitor of epidermal growth factor receptor (EGFR) kinase, completely blocked the effect of BK, suggesting an essential role of EGFR in ERK1/2 activation by BK. Immunoprecipitation/Western blot studies revealed that BK stimulated tyrosine phosphorylation of EGFR, its association with an adapter molecule Grb2, and complex formation between Grb2 and the adapter protein Shc. Activation studies of monomeric G protein Ras showed that BK-induced stimulation of Ras was dependent on EGFR tyrosine kinase activity. These studies demonstrate that BK stimulates Ras-dependent activation of ERK1/2 in mIMCD-3 cells via transactivation of EGFR through a novel mechanism.

Footnotes

  • This work was supported by grants from the Department of Veterans Affairs (Merit Award to M.N.G. and an REAP Award to Y.V.M. and M.N.G.), and by Grant K01-DK02694 from the National Institutes of Health (to Y.V.M.).

  • DOI: 10.1124/jpet.102.043943

  • Abbreviations:
    BK
    bradykinin
    IMCD
    inner medullary collecting duct
    MAPK
    mitogen-activated protein kinase
    ERK
    extracellular signal-regulated protein kinase
    RTK
    receptor tyrosine kinase
    GPCR
    G protein-coupled receptor
    MEK
    mitogen-activated protein kinase/extracellular signal-regulated kinase kinase
    PKC
    protein kinase C
    CaM
    calmodulin
    DMEM
    Dulbecco's modified Eagle's medium
    EGF
    epidermal growth factor
    EGFR
    epidermal growth factor receptor
    F-12
    Ham's F-12 nutrient mixture
    Grb2
    growth factor receptor binding protein 2
    Jak2
    Janus kinase 2
    LPA
    lysophosphatidic acid
    PI3K
    phosphatidylinositol 3-kinase
    PLC
    phospholipase C
    PMA
    phorbol 12-myristate 13-acetate
    PTX
    pertussis toxin
    RIPA
    radioimmune precipitation buffer
    Shc
    Src homology and collagen protein
    Sos
    son of sevenless (Ras exchange factor)
    VSMC
    vascular smooth muscle cells
    PAGE
    polacrylamide gel electrophoresis
    BAPTA
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
    TxA2
    thromboxane A2
    • Received September 4, 2002.
    • Accepted October 31, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 304 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 3
1 Mar 2003
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Research ArticleCELLULAR AND MOLECULAR

Bradykinin B2 Receptor Activates Extracellular Signal-Regulated Protein Kinase in mIMCD-3 Cells via Epidermal Growth Factor Receptor Transactivation

Yurii V. Mukhin, Evgeny A. Garnovsky, Michael E. Ullian and Maria N. Garnovskaya
Journal of Pharmacology and Experimental Therapeutics March 1, 2003, 304 (3) 968-977; DOI: https://doi.org/10.1124/jpet.102.043943

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Research ArticleCELLULAR AND MOLECULAR

Bradykinin B2 Receptor Activates Extracellular Signal-Regulated Protein Kinase in mIMCD-3 Cells via Epidermal Growth Factor Receptor Transactivation

Yurii V. Mukhin, Evgeny A. Garnovsky, Michael E. Ullian and Maria N. Garnovskaya
Journal of Pharmacology and Experimental Therapeutics March 1, 2003, 304 (3) 968-977; DOI: https://doi.org/10.1124/jpet.102.043943
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