| First Author | Hooker E | Year | 2017 |
| Journal | Biochem J | Volume | 474 |
| Issue | 9 | Pages | 1509-1528 |
| PubMed ID | 28275114 | Mgi Jnum | J:246700 |
| Mgi Id | MGI:5925147 | Doi | 10.1042/BCJ20160832 |
| Citation | Hooker E, et al. (2017) Binding and inhibition of the ternary complex factor Elk-4/Sap1 by the adapter protein Dok-4. Biochem J 474(9):1509-1528 |
| abstractText | The adapter protein Dok-4 (downstream of kinase-4) has been reported as both an activator and inhibitor of Erk and Elk-1, but lack of knowledge about the identity of its partner molecules has precluded any mechanistic insight into these seemingly conflicting properties. We report that Dok-4 interacts with the transactivation domain of Elk-4 through an atypical phosphotyrosine-binding domain-mediated interaction. Dok-4 possesses a nuclear export signal and can relocalize Elk-4 from nucleus to cytosol, whereas Elk-4 possesses two nuclear localization signals that restrict interaction with Dok-4. The Elk-4 protein, unlike Elk-1, is highly unstable in the presence of Dok-4, through both an interaction-dependent mechanism and a pleckstrin homology domain-dependent but interaction-independent mechanism. This is reversed by proteasome inhibition, depletion of endogenous Dok-4 or lysine-to-arginine mutation of putative Elk-4 ubiquitination sites. Finally, Elk-4 transactivation is potently inhibited by Dok-4 overexpression but enhanced by Dok-4 knockdown in MDCK renal tubular cells, which correlates with increased basal and EGF-induced expression of Egr-1, Fos and cylcinD1 mRNA, and cell proliferation despite reduced Erk activation. Thus, Dok-4 can target Elk-4 activity through multiple mechanisms, including binding of the transactivation domain, nuclear exclusion and protein destabilization, without a requirement for inhibition of Erk. |
