Stress-activated protein kinase-3 interacts with the PDZ domain of alpha1-syntrophin. A mechanism for specific substrate recognition.
Mechanisms for selective targeting to unique subcellular sites play an important role in determining the substrate specificities of protein kinases. Here we show that stress-activated protein kinase-3 (SAPK3, also called ERK6 and p38gamma), a member of the mitogen-activated protein kinase family that is abundantly expressed in skeletal muscle, binds through its carboxyl-terminal sequence -KETXL to the PDZ domain of alpha1-syntrophin. SAPK3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the PDZ domain of alpha1-syntrophin. In skeletal muscle SAPK3 and alpha1-syntrophin co-localize at the neuromuscular junction, and both proteins can be co-immunoprecipitated from transfected COS cell lysates. Phosphorylation of a PDZ domain-containing protein by an associated protein kinase is a novel mechanism for determining both the localization and the substrate specificity of a protein kinase.
Hasegawa
M
M
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom.
Cuenda
A
A
Spillantini
M G
MG
Thomas
G M
GM
Buée-Scherrer
V
V
Cohen
P
P
Goedert
M
M
D000595:Amino Acid Sequence; D000818:Animals; D002038:Bungarotoxins / Q000378:metabolism; D019556:COS Cells; D002135:Calcium-Binding Proteins; D005455:Fluorescent Antibody Technique; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D048291:Mitogen-Activated Protein Kinase 12; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D009469:Neuromuscular Junction / Q000201:enzymology / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D002038:Bungarotoxins; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D010446:Peptide Fragments; C091825:syntrophin alpha1; D011494:Protein Kinases; D048291:Mitogen-Activated Protein Kinase 12; D020928:Mitogen-Activated Protein Kinases