RRC ID 12186
Author Nosaka Y, Arai A, Miyasaka N, Miura O.
Title CrkL mediates Ras-dependent activation of the Raf/ERK pathway through the guanine nucleotide exchange factor C3G in hematopoietic cells stimulated with erythropoietin or interleukin-3.
Journal J. Biol. Chem.
Abstract CrkL is an SH2 and SH3 domain-containing adaptor protein implicated in pathogenesis of chronic myelogenous leukemia. Here, we demonstrate that overexpression of CrkL enhances the erythropoietin (Epo)- or interleukin (IL)-3-induced activation of Elk-1 and the c-fos gene promoter activity in 32D/EpoR-Wt cells. Moreover, the Epo-induced activation of ERK1 and ERK2 was augmented and prolonged in cells inducibly overexpressing CrkL. A moderate increase in Epo-induced activation of JNK was also observed in cells overexpressing CrkL. Overexpression of C3G enhanced the Elk-1 activation synergistically with CrkL, while a C3G mutant lacking the guanine nucleotide exchange domain showed an inhibitory effect. Studies using a dominant negative Ha-Ras mutant demonstrated that the Elk-1 and ERK2 activation enhanced by CrkL and C3G was dependent on Ras. Consistent with this, the Epo-induced activation of Ras was augmented in cells inducibly overexpressing CrkL. Most importantly, a CrkL mutant defective in the SH2 or N-terminal SH3 domain showed an inhibitory effect on the Epo-induced activation of ERK2. These data indicate that the CrkL-C3G complex plays a role in Epo- or IL-3-induced, Ras-dependent activation of the Raf/ERK pathway leading to the activation of Elk-1 and the c-fos gene transcription.
Volume 274(42)
Pages 30154-62
Published 1999-10-15
PMID 10514505
MeSH Adaptor Proteins, Signal Transducing* Animals Bone Marrow Cells / drug effects* Bone Marrow Cells / enzymology Bone Marrow Cells / metabolism DNA-Binding Proteins* Enzyme Activation Erythropoietin / pharmacology* Genes, fos Guanine Nucleotide-Releasing Factor 2 / metabolism* Interleukin-3 / pharmacology* MAP Kinase Signaling System* Mice Nuclear Proteins / metabolism* Promoter Regions, Genetic Proto-Oncogene Proteins / metabolism Recombinant Proteins / pharmacology Transcription Factors* ets-Domain Protein Elk-1 ras Proteins / metabolism* src Homology Domains
IF 4.011
Times Cited 49
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
DNA material pZRmERK2 (RDB01796)