Stress-activated kinases regulate protein stability

Abstract

Proteasome inhibitors have been used to demonstrate that many proteins of the signal transduction pathways are regulated by degradation via the ubiquitin-proteasome pathway. The key question is what events target speci®c proteins for ubiquitination at one time and prevent ubiquitination at other times? In this review, we develop the notion that there is a direct relationship between the phosphorylation/dephosphorylation cascade of the signal transduction pathways and the targeting of the regulatory proteins for ubiquitination. We present examples where phosphorylation appears to alter the interaction between the targeting systems and the substrate by modifying the targeting system, the substrate, or both. These interacting systems are seen in the response of p53, c-jun and ATF-2 in cells subjected to stress or DNA damage and to the normal regulated response in a variety of pathways including the IkBNFkB and JAK-STAT pathways. The interweaving of the two post-translational networks, phosphorylation and ubiquitination, provides a powerful insight into global regulatory control pathways.

Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor

“…Addition of polyubiquitin chains is often regulated by phosphorylation or, in some instances, by dephosphorylation of serine(s) or threonine(s) in the vicinity of lysines that are substrate for ubiquitination (reviewed by Fuchs et al 35 ). Alignment of human Bfl-1 with its mouse homolog A1 identified serine 152 and threonines 156 and 161 to be conserved in both species (Figure 4c).…”

Role of the ATFa/JNK2 complex in Jun activation

“…It has indeed been shown that phosphorylation by JNK protects substrates from JNK-targeted ubiquitinylation and subsequent proteolytic degradation (Fuchs et al, 1996(Fuchs et al, , 1997Musti et al, 1997). Interestingly, we recently identi®ed UBC9, a ubiquitin conjugating enzyme (Kovalenko et al, 1996), as a potential partner of ATFa, using a two-hybrid screen in yeast (unpublished results).…”

“…The JNKs were initially identi®ed by their ability to bind the N-terminus of the c-Jun protein, on a site (now de®ned as the docking site) encompassing amino acids 33 ± 47, and to subsequently phosphorylate the Ser63 and Ser73 residues (Whitmarsh and Davis, 1996;Minden and Karin, 1997). Phosphorylation of these sites stimulates the ability of c-Jun to activate transcription of speci®c target genes by a mechanism which remains largely unknown: it has been proposed, for example, that this phosphorylation may indirectly protect c-Jun from ubiquitinylation, thereby prolonging its half-life (Fuchs et al, 1996(Fuchs et al, , 1997; alternatively, this phosphorylation may induce the dephosphorylation of Thr231, Ser243 and Ser249 residues and, as a consequence, increase cJun DNA-binding activity (Papavassiliou et al, 1995).…”

Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1

“…In addition to the now classical cases of the inhibitor of nuclear factor kB (IkB) family (Karin and Ben-Neriah, 2000;Chen, 2005;Krappmann and Scheidereit, 2005) and cyclins (Lin et al, 2006a), other examples of proteins whose (poly)ubiquitination is stimulated by their phosphorylation include the type I interferon receptor IFNAR1 (Kumar et al, 2004), the transcription factor STAT1 (Kim and Maniatis, 1996), the antiapoptotic protein Bcl-2 (Lin et al, 2006b) and bcatenin (Aberle et al, 1997;Orford et al, 1997). On the other hand, phosphorylation can inhibit the ubiquitination of other proteins such as the proto-oncogenes c-jun (Musti et al, 1997;Fuchs et al, 1998), c-fos (Okazaki and Sagata, 1995) and c-mos (Nishizawa et al, 1993).…”