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CRIPak, a novel endogenous Pak1 inhibitor

Oncogene volume 25, pages 1311–1319 (2006)Cite this article

Abstract

p21-activated protein kinase 1 (Pak1) plays an important role in several cellular processes, including cytoskeleton reorganization, promotion of the cell survival, and the estrogen receptor (ER) signaling. Pak1 expression and activity is deregulated in a number of cancers. Pak1 is activated by a variety of physiological signals; however, less is known about the negative regulators of Pak1. Here, we report a negative regulator of Pak1. By performing a yeast two-hybrid screen of a mammary gland library, we identified cysteine-rich inhibitor of Pak1 (CRIPak) as a novel Pak1-interacting protein. We found that CRIPak is an intronless gene that localized to chromosome 4p16.3. It contains 13 zinc-finger domains and has three trypsin inhibitor-like, cysteine-rich domains and is widely expressed in a number of human cells and tissues. We further found that CRIPak interacted with Pak1 through the N-terminal regulatory domain and inhibited Pak1 kinase in both in vitro and in vivo assays. CRIPak inhibited Pak1-mediated LIM kinase activation and enhancement of ER transactivation. Conversely, selective inhibition of the endogenous CRIPak resulted in an increased Pak1 activity, and consequently, increased cytoskeleton remodeling and Pak1-mediated ER transactivation activity. The hormonal stimulation of cells enhanced CRIPak expression and promoted its colocalization with ER in the nuclear compartment. Our findings suggest that CRIPak is a novel negative regulator of the Pak1 and has a role in the modulation of Pak1-mediated ER transactivation in breast cancer cells.

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Acknowledgements

We thank Dr Bruce J Mayer for the PEBG vector, and Dr Ratna K Vadlamudi for helpful discussion. This study was supported by NIH Grants CA90970, CA98823 and CA80066 (RK).

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  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A H Talukder, Q Meng & R Kumar

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  1. A H Talukder
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  2. Q Meng
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Correspondence to R Kumar.

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Talukder, A., Meng, Q. & Kumar, R. CRIPak, a novel endogenous Pak1 inhibitor. Oncogene 25, 1311–1319 (2006). https://doi.org/10.1038/sj.onc.1209172

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