Human Mitogen-activated Protein Kinase Kinase 7 (MKK7) Is a Highly Conserved c-Jun N-terminal Kinase/Stress-activated Protein Kinase (JNK/SAPK) Activated by Environmental Stresses and Physiological Stimuli

Abstract

We report the cloning of a novel human activator of c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 7 (MKK7). The mRNA for MKK7 is widely expressed in humans and mice and encodes a 47-kDa protein (419 amino acids), as determined by immunoblotting endogenous MKK7 with an antibody raised against its N terminus. The kinase domain of MKK7 is closely related to a Drosophila JNK kinase dHep (69% identity) and to a newly identified ortholog from Caenorhabditis elegans (54% identity), and was more distantly related to MKK4, MKK3, and MKK6. MKK7 phosphorylated and activated JNK1 but failed to activate p38 MAPK in co-expression studies. In hematopoietic cells, endogenous MKK7 was activated by treatment with the growth factor interleukin-3 (but not interleukin-4), or by ligation of CD40, the B-cell antigen receptor, or the receptor for the Fc fragment of immunoglobulin. MKK7 was also activated when cells were exposed to heat, UV irradiation, anisomycin, hyperosmolarity or the pro-inflammatory cytokine tumor necrosis factor-␣. Co-expression of constitutively active mutants of RAS, RAC, or CDC42 in HeLa epithelial cells or of RAC or CDC42 in Ba/F3 factor-dependent hematopoietic cells also activated MKK7, suggesting that MKK7 will be involved in many physiological pathways.

Role of MEKK2-MEK5 in the regulation of TNF-α gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells

“…Two specific JNK-activating MAPKKs, MAP kinase kinase 4 (MKK4) (JNKK1) and MKK7 (JNKK2), are known to directly activate JNK (5,6). In different cell types, MKK4 and MKK7 may be differentially activated by external stimuli such as TNF-␣ or cellular stresses, and distinct upstream activators have been implicated in the activation of these responses (6,7).…”

“…In addition to MKK4, MKK7 has also been demonstrated to serve as a potent activator of JNK in cell types other than mast cells (5,26). To assess the role of MKK7 in JNK activation in MKK4Ϫ͞Ϫ ESMC mast cells, in vitro kinase assays with anti-MKK7 immunoprecipitates were performed.…”

Stimulation of MAPK cascades by insulin and osmotic shock: lack of an involvement of p38 mitogen-activated protein kinase in glucose transport in 3T3-L1 adipocytes.

“…Both the threonine and tyrosine residues are phosphorylated by a dualspecificity kinase or MAPK (mitogen-activated ERK-activating kinase [MEK] or MAPK kinase [MKK]). The central residue in the Thr-Xaa-Tyr motif allows for selective activation by different MKKs, such that MEK1 and MEK2 selectively phosphorylate and activate the ERKs; MKK4/SAPK kinase (SEK) 1 and MKK7 phosphorylate and activate JNK; MKK3 and MKK6 phosphorylate and activate p38 MAPK (4)(5)(6)(7)(8)(9). Despite the prevailing view of the selectivity of these kinases, a growing body of evidence indicates that these pathways overlap.…”

Lack of EGF receptor contributes to drug sensitivity of human germline cells

“…Low level of EGFR expression in germline tumour cells may be linked to their drug sensitivity and supports a positive role for EGFR in drug resistance of cancer. The latter may be explained by the fact that EGF and its receptor activate the JNK signalling pathway that leads to the induction of genes involved in DNA repair and cellular redox (Adler et al, 1992;Foltz et al, 1998;Roulston et al, 1998).…”