File(s) under permanent embargo
The very C-terminus of PRK1/PKN is essential for its activation by RhoA and downstream signaling
journal contribution
posted on 2006-09-01, 00:00 authored by W Lim, B Tan, Y Zhu, S Zhou, J Armstrong, Q Li, Q Dong, E Chan, D Smith, C Verma, S L Tan, Wei DuanWei DuanPRK1 is a lipid- and Rho GTPase-activated serine/threonine protein kinase implicated in the regulation of receptor trafficking, cytoskeletal dynamics and tumorigenesis. Although Rho binding has been mapped to the HR1 region in the regulatory domain of PRK1, the mechanism involved in the control of PRK1 activation following Rho binding is poorly understood. We now provide the first evidence that the very C-terminus beyond the hydrophobic motif in PRK1 is essential for the activation of this kinase by RhoA. Deletion of the HR1 region did not completely abolish the binding of PRK1-ΔHR1 to GTPγS-RhoA nor the activation of this mutant by GTPγS-RhoA in vitro. In contrast, removing of the last six amino acid residues from the C-terminus of PRK1 or truncating of a single C-terminal residue from PRK1-ΔHR1 completely abrogated the activation of these mutants by RhoA both in vitro and in vivo. The critical dependence of the very C-terminus of PRK1 on the signaling downstream of RhoA was further demonstrated by the failure of the PRK1 mutant lacking its six C-terminal residues to augment lisophosphatidic acid-elicited neurite retraction in neuronal cells. Thus, we show that the HR1 region is necessary but not sufficient in eliciting a full activation of PRK1 upon binding of RhoA. Instead, such activation is controlled by the very C-terminus of PRK1. Our results also suggest that the very C-terminus of PRK1, which is the least conserved among members of the protein kinase C superfamily, is a potential drug target for pharmacological intervention of RhoA-mediated signaling pathways
History
Journal
Cellular signallingVolume
18Issue
9Pagination
1473 - 1481Publisher
Elsvier Inc.Location
Amsterdam, NetherlandsPublisher DOI
ISSN
0898-6568eISSN
1873-3913Language
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2005, Elsevier Inc.Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC