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- Title
Sustained Mitogen-Activated Protein Kinase Activation Is Induced by Transforming erbB Receptor Complexes.
- Authors
Wu, Chuan-Jin; Qian, Xiaolan; O'Rourke, Donald M.
- Abstract
We used a genetic approach to characterize features of mitogen-activated protein kinase (MAPK) activation occurring as a consequence of expression of distinct erbB receptor combinations in transformed human cells. Kinase-deficient erbB proteins reduced epidermal growth factor (EGF)-induced tyrosine phosphorylation of endogenous Shc proteins and also reduced immediate and sustained EGF-induced ERK MAPK activities in human glioblastoma cells, although basal ERK MAPK activities were unaffected. Basal and EGF-induced JNK and p38 MAPK kinase activities were equivalent in parental cancer cells and EGFR-inhibited subclones. When ectopically overexpressed in murine fibroblasts and human glioblastoma cells, a constitutively activated human EGF receptor oncoprotein (Delta EGFR) induced EGF-independent elevation of basal ERK MAPK activity. Basal JNK MAPK kinase activity was also specifically induced by Delta EGFR, which correlated with increased phosphorylation of a 54-kDa JNK2 protein observed in Delta EGFR-containing cells. The JNK activities in response to DNA damage were comparably increased in cells containing wildtype EGFR or Delta EGFR. Consistent with the notion that transforming erbB complexes induce sustained and unregulated MAPK activities, coexpression of p185neu and EGFR proteins to levels sufficient to transform murine fibroblasts also resulted in prolonged EGF-induced ERK in vitro kinase activation. Transforming erbB complexes, including EGFR homodimers, Delta EGFR homodimers, and p185neu/EGFR heterodimers, appear to induce sustained, unattenuated activation of MAPK activities that may contribute to increased transformation and resistance to apoptosis in primary human glioblastoma cells.
- Subjects
PROTEIN kinases; GENE expression
- Publication
DNA & Cell Biology, 1999, Vol 18, Issue 10, p731
- ISSN
1044-5498
- Publication type
Article
- DOI
10.1089/104454999314872