Extracellular Signal-Regulated Kinase 1c (ERK1c), a Novel 42-Kilodalton ERK, Demonstrates Unique Modes of Regulation, Localization, and Function

Abstract

Extracellular signal-regulated kinases (ERKs) are signaling molecules that regulate many cellular processes. We have previously identified an alternatively spliced 46-kDa form of ERK1 that is expressed in rats and mice and named ERK1b. Here we report that the same splicing event in humans and monkeys causes, due to sequence differences in the inserted introns, the production of an ERK isoform that migrates together with the 42-kDa ERK2. Because of the differences of this isoform from ERK1b, we named it ERK1c. We found that its expression levels are about 10% of ERK1. ERK1c seems to be expressed in a wide variety of tissues and cells. Its activation by MEKs and inactivation by phosphatases are slower than those of ERK1, which is probably the reason for its differential regulation in response to extracellular stimuli. Unlike ERK1, ERK1c undergoes monoubiquitination, which is increased with elevated cell density concomitantly with accumulation of ERK1c in the Golgi apparatus. Elevated cell density also causes enhanced Golgi fragmentation, which is facilitated by overexpression of native ERK1c and is prevented by dominant-negative ERK1c, indicating that ERK1c mediates cell density-induced Golgi fragmentation. The differential regulation of ERK1c extends the signaling specificity of MEKs after stimulation by various extracellular stimuli.Extracellular signal-regulated kinases (ERKs) 1 and 2 (ERK1 and ERK2, which are 44 and 42 kDa, respectively) are key signaling enzymes that are activated by a large number of extracellular stimuli and play an important role in physiological processes, such as proliferation, differentiation, and development (28,32,40). ERKs are ubiquitously expressed and share a high degree of similarity (85% [5]). Under most conditions, ERK1 and ERK2 demonstrate identical patterns of regulation, which is mainly manifested in their activation by MEK1 and MEK2 (MEKs) through the phosphorylation of threonine and tyrosine in their characteristic Thr-Glu-Tyr motif. These two isoforms also share substrate recognition and subcellular localization, suggesting a redundant functionality of these ERKs (34). Consistent with these observations, ERK1 knockout mice are viable, without any apparent defects, which might be due to increased levels of ERK2 expression that compensate for the lack of ERK1 (24). On the other hand, ERK2 knockout mice die as embryos, due to failure in mesoderm induction, which is not compensated for by ERK1 that is not expressed at this stage of embryonic development (45). The ability of the ERKs to transmit different and even opposing signals despite the pronounced similarities between the two ERK isoforms raises the question of how is the specificity of the different signals regulated.It has previously been demonstrated that signaling specificity is determined by duration and strength of the signals (23) as well as compartmentalization (29,39). Another mechanism that contributes to specificity is the extensive cross talk and interplay between the ERK cascade and other intracellular signal...

The E3 Ubiquitin Ligase Activity of Arabidopsis PLANT U-BOX17 and Its Functional Tobacco Homolog ACRE276 Are Required for Cell Death and Defense

“…Similar ubiquitination-mediated activation of signaling components such as kinases and transcription factors has been reported in mammals and yeast (Muratani and Tansey, 2003;Aebersold et al, 2004). …”

A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

“…Thus, elucidation of the components by which different signals can be transmitted by similar signaling cascades is important. To date, there are two ERK genes (ERK1,2), and those encode two main proteins, p44 and p42 (19), and a few alternatively spliced forms such as the rodent ERK1b (21) and the primate ERK1c (22). We suggest that the major 50-kDa ERK that was observed in different mouse strains (SJL, BALB/c, and C57BL/6) after immunization with the myasthenogenic peptides or the TAChR and that was up-regulated by the dual APL may be an alternative spliced form of ERK.…”

The ERK Cascade: Distinct Functions within Various Subcellular Organelles

“…63 Interestingly, a similar splicing event also occurs in primates; in this case, however, the insert consists of 103 base pairs that are followed by a stop codon, which leads to the translation of a 42-kDa protein termed ERK1c. 40 It was shown that ERK1c is expressed in most human cells, is activated primarily by MEK1b, and is unique in regulating mitotic Golgi fragmentation. 62,64 Other ERK1/2 splice variants, such as ERK1d (unpublished) and ERK2b, 12 seem to be generated as well, and extend the specificity of the ERK1/2 cascade, as described below.…”

“…Each gene encodes one main product, which are the primary 44-kDa (ERK1) and 42-kDa (ERK2) proteins. In addition, these genes encode several splice variants, including ERK1b (46 kDa 39 ), ERK1c (42 kDa 40 ), and others that will be described below. The MEK1/2-mediated phosphorylation of ERK1/2 on the Thr and Tyr residues in their Thr-Xaa-Tyr signature motif (Thr202 and Tyr204 in human ERK1 41 ) is the mechanism that induces their full activation.…”