MEKK2 Associates with the Adapter Protein Lad/RIBP and Regulates the MEK5-BMK1/ERK5 Pathway

Abstract

The mitogen-activated protein kinase (MAPK) 1 pathways transduce various extracellular stimuli into distinct intracellular responses. The core component of such a MAPK module is a set of three sequential kinases that are evolutionarily conserved in eukaryotes from unicellular yeast to plants and animals. In mammalian cells, three distinguishable MAPK modules have been well described; they are the extracellular signalregulated kinases 1 and 2 (ERK1/2), the c-Jun N-terminal kinase (JNK), and the p38 pathways. The MAPK pathways regulate cell growth, differentiation, adaptation to the environment, and apoptosis in response to a great number of stimuli, including cytokines and various stresses (1-3). The MAPKs also control numerous regulatory processes during development and homeostasis (4 -6).Our laboratory previously cloned two MAPK kinase kinases, designated MEKK2 and MEKK3 (7). MEKK2 and MEKK3 are extremely homologous (94% conserved) in their catalytic domains, but their regulatory N-terminal sequences are quite divergent, with only 65% homology, predicting that they perform similar as well as different cellular tasks. In this regard, Schaefer et al. (8) showed that T cell MEKK2 but not MEKK3 is activated and translocates to the plasma membrane at the contact with antigen-loaded presenting cells. Thus, although MEKK2 and MEKK3 are both mediators of signal transduction to the MAPK pathways, they are subject to stimulus-and cell type-specific regulation. A differential involvement of MEKK2 and MEKK3 in cellular signaling has also been demonstrated by our recent finding that MEKK2 but not MEKK3 regulates the activity of the protein kinase C-related kinase PRK2 (9).Big mitogen-activated protein kinase 1 (BMK1)/ERK5 was recently cloned as a novel member of the MAPK family (10, 11). Like ERK1/2, BMK1/ERK5 has a TEY sequence in its dual phosphorylation motif; however, other structural features such as a large regulatory C terminus and a unique loop 12 domain distinguish BMK1/ERK5 from ERK1/2 and other MAP kinases (10). This predicts that the regulation and function of BMK1/ ERK5 are distinct from those of other MAPKs. In this regard, Zhou et al. (11) showed that BMK1/ERK5 interacts specifically with MEK5 but not its closely related MAPK kinases MEK1 and MEK2, suggesting that MEK5/BMK1 represents a separate signaling module. Indeed, MEK5 selectively phosphorylates and activates BMK1/ERK5 (12, 13), and its activity is required for the activation of BMK1/ERK5 induced by extracellular signals, including growth factors, serum, oxidative stress, and hyperosmolarity (13,14). Consistent with the notion that MEK5/BMK1 lies in a signal transduction pathway

ERK5 regulation in naïve T‐cell activation and survival

“…In addition, three studies have shown that ERK5 can be activated in T cells downstream of TCR-mediated signalling [28][29][30]. It has also been reported that MEKK2, an activator of the ERK5 pathway, can interact with LAD/RIBP, an Lck-interacting adaptor protein, which is recruited to the TCR complex [18]. It has been proposed that ERK5 may control the expression of specific immediate early (IE) genes in T cells by regulating the activity of MEF2 transcription factors [9].…”

“…One possibility is MEKK3, as mouse knockouts of MEKK3 [16] have a similar phenotype to that of ERK5 knockouts. In addition, MEKK3 has been shown to activate ERK5 in transfection experiments in Hek293 cells [17] and kinase inactive MEKK3 blocks ERK5 activation in Cos7 cells [18].…”

“…One possibility is MEKK3, as mouse knockouts of MEKK3 [16] have a similar phenotype to that of ERK5 knockouts. In addition, MEKK3 has been shown to activate ERK5 in transfection experiments in Hek293 cells [17] and kinase inactive MEKK3 blocks ERK5 activation in Cos7 cells [18].ERK5 is expressed in most cell types; however, its precise physiological roles are not completely understood. ERK5 has been shown to promote both the proliferation and survival of several cell lines [10,19].…”

Aberrant Extracellular Signal-Regulated Kinase (ERK) 5 Signaling in Hippocampus of Suicide Subjects

“…A number of other extracellular stimuli, such as epidermal growth factor and G-protein-coupled receptors, also activate ERK5 (Kato et al, 1998;Marinissen et al, 1999). Activation of ERK5 requires phosphorylation of Thr-219 and Tyr-221 residues by upstream MAPK kinase5 (MEK5), which in turn is activated by MEKK2, MEKK3, and Cot (Chao et al, 1999;Chiariello et al, 2000;Sun et al, 2001). ERK5, although activated by a similar Thr-Glu-Tyr dual phosphorylation motif as are ERK1/2 and ERK7, however, contains a unique loop-12 structure and an unusually large C-terminal nonkinase domain, which is absent in other types of MAPKs.…”

Stat3 upregulates MEK5 expression in human breast cancer cells

“…Some reports demonstrated that MEK5 was regulated by TNFa/JNK signal pathway (Dent et al, 2003;Yoshizumi et al, 2003). MEKK2 and MEKK3 have been demonstrated as MEK5/ERK5 direct upstream regulators (Chao et al, 1999;Chayama et al, 2001;Sun et al, 2001). It has been proven that MEK5 acts through regulating MEF2C, a member of the MEF2 transcription factor family (Kato et al, 1997).…”