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p38 MAPK-mediated activation of NF-κB by the RhoGEF domain of Bcr

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Abstract

The oncogenic fusion protein p210 Bcr-Abl is causally associated with virtually all cases of chronic myelogenous leukemia. The wild-type Bcr product has several recognizable structural and functional motifs including a domain that contains guanine nucleotide exchange activity for Rho family GTPases (DH/PH domain). Although this domain is retained within p210 Bcr-Abl, it has no known signaling activities in vivo. Here we report that a fragment of Bcr that encodes the isolated DH/PH domain is a potent activator of the NF-κB transcription factor. Within the context of full length Bcr, this activity is regulated by proximal flanking sequences that suppress the DH/PH domain encoded guanine nucleotide exchange activity. NF-κB activation by Bcr is not mediated by nuclear translocation, but rather by p38 mitogen-activated protein kinase (MAPK)-dependent modification of the RelA/p65 transactivation domain. Although we were able to demonstrate that Bcr can function as an exchange factor for Cdc42 in vivo, NF-κB activation appears to occur via a Cdc42-independent mechanism. These studies constitute direct evidence that the Bcr RhoGEF domain can function in vivo, and identify a new signaling activity that may contribute to the transforming potential of p210 Bcr-Abl.

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Acknowledgements

This work was supported by Public Health Service grant CA-77493 (IP Whitehead) from the National Cancer Institute.

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  1. Malgorzata Korus and Gwendolyn M Mahon: M Korus and G M Mahon contributed equally to this work

Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics, UMDNJ–New Jersey Medical School, Newark, 07103, New Jersey, NJ, USA

    Malgorzata Korus, Gwendolyn M Mahon, Li Cheng & Ian P Whitehead

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  1. Malgorzata Korus
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  2. Gwendolyn M Mahon
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  3. Li Cheng
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  4. Ian P Whitehead
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Correspondence to Ian P Whitehead.

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Korus, M., Mahon, G., Cheng, L. et al. p38 MAPK-mediated activation of NF-κB by the RhoGEF domain of Bcr. Oncogene 21, 4601–4612 (2002). https://doi.org/10.1038/sj.onc.1205678

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