Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7

Author:

FLEMING Yvonne1,ARMSTRONG Christopher G.2,MORRICE Nick1,PATERSON Andrew2,GOEDERT Michel3,COHEN Philip1

Affiliation:

1. MRC Protein Phosphorylation Unit, Department of Biochemistry, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.

2. Division of Signal Transduction Therapy, Department of Biochemistry, University of Dundee, Dundee DD1 5EH, Scotland, U.K.

3. MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, U.K.

Abstract

Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1α1, JNK2α2 and JNK3α1). For this reason, MKK4 and MKK7 together produce a synergistic increase in the activity of each SAPK1/JNK isoform in vitro. The MKK7β variant, which is several hundred-fold more efficient in activating all three SAPK1/JNK isoforms than is MKK7α´, is equally specific for Thr-183. MKK7 also phosphorylates JNK2α2 at Thr-404 and Ser-407 in vitro, Ser-407 being phosphorylated much more rapidly than Thr-183 in vitro. Thr-404/Ser-407 are phosphorylated in unstimulated human KB cells and HEK-293 cells, and phosphorylation is increased in response to an osmotic stress (0.5M sorbitol). However, in contrast with Thr-183 and Tyr-185, the phosphorylation of Thr-404 and Ser-407 is not increased in response to other agonists that activate MKK7 and SAPK1/JNK, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as CK2, which also phosphorylates Thr-404 and Ser-407 in vitro. MKK3, MKK4 and MKK6 all show a strong preference for phosphorylation of the tyrosine residue of the Thr-Gly-Tyr motifs in their known substrates SAPK2a/p38, SAPK3/p38γ and SAPK4/p38δ. MKK7 also phosphorylates SAPK2a/p38 at a low rate (but not SAPK3/p38γ or SAPK4/p38δ), and phosphorylation occurs exclusively at the tyrosine residue, demonstrating that MKK7 is intrinsically a ‘dual-specific’ protein kinase.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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