Inhibition of cap-dependent translation via phosphorylation of eIF4G by protein kinase Pak2

Ling, Jun, Morley, Simon J and Traugh, Jolinda A (2005) Inhibition of cap-dependent translation via phosphorylation of eIF4G by protein kinase Pak2. EMBO Journal, 24 (23). pp. 4094-4105. ISSN 0261-4189

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Translation is downregulated in response to a variety of moderate stresses, including serum deprivation, hyperosmolarity and ionizing radiation. The cytostatic p21-activated protein kinase 2 (Pak2)/gamma-PAK is activated under the same stress conditions. Expression of wild-type Pak2 in cells and addition of Pak2 to reticulocyte lysate inhibit translation, while kinase-inactive mutants have no effect. Pak2 binds to and phosphorylates initiation factor (eIF)4G, which inhibits association of eIF4E with m7GTP, reducing initiation. The Pak2-binding site maps to the region on eIF4G that contains the eIF4E-binding site; Pak2 and eIF4E compete for binding to this site. Using an eIF4G-depleted reticulocyte lysate, reconstitution with mock-phosphorylated eIF4G fully restores translation, while phosphorylated eIF4G reduces translation to 37%. RNA interference releases Pak2-induced inhibition of translation in contact-inhibited cells by 2.7-fold. eIF4G mutants of the Pak2 site show that S896D inhibits translation, while S896A has no effect. Activation of Pak2 in response to hyperosmotic stress inhibits cap-dependent, but not IRES-driven, initiation. Thus, a novel pathway for mammalian cell stress signaling is identified, wherein activation of Pak2 leads to inhibition of cap-dependent translation through phosphorylation of eIF4G.

Item Type: Article
Additional Information: This is the first demonstration of a novel role for PAK2 in controlling translation initiation, identifying a novel phosphorylation site which reduced cap complex assembly. SM provided all purified proteins, directed some of the research and actively collaborated in the writing of the manuscript with Prof. J. Traugh.
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Simon Morley
Date Deposited: 06 Feb 2012 20:41
Last Modified: 14 Jun 2012 08:42
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