Phosphorylation of p38 by GRK2 at the docking groove unveils a novel mechanism for inactivating p38MAPK.
p38 Mitogen-activated protein kinases (MAPK) are a family of Ser/Thr kinases that regulate important cellular processes such as stress responses, differentiation, and cell-cycle control . Activation of MAPK is achieved through a linear signaling cascade in which upstream kinases (MAPKKs) dually phosphorylate MAPKs at a conserved 3-amino-acid motif (Thr-X-Tyr) . G-protein-coupled receptor kinases (GRKs) are known to selectively phosphorylate G-protein-coupled receptors (GPCRs) and thus trigger desensitization . We report that GRK2 is a novel inactivating kinase of p38MAPK. p38 associates with GRK2 endogenously and is phosphorylated by GRK2 at Thr-123, a residue located at its docking groove. Mimicking phosphorylation at this site impairs the binding and activation of p38 by MKK6 and diminishes the capacity of p38 to bind and phosphorylate its substrates. Accordingly, p38 activation is decreased or increased when cellular GRK2 levels are enhanced or reduced, respectively. Changes in GRK2 levels and activity can modify p38-dependent processes such as differentiation of preadipocytic cells and LPS-induced cytokine release, enhanced in macrophages from GRK2(+/-) mice. Phosphorylation of p38 at a region key for its interaction with different partners uncovers a new mechanism for the regulation of this important family of kinases.
Peregrin
Sandra
S
Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Jurado-Pueyo
Maria
M
Campos
Pedro M
PM
Sanz-Moreno
Victoria
V
Ruiz-Gomez
Ana
A
Crespo
Piero
P
Mayor
Federico
F
Murga
Cristina
C
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D017931:DNA Primers; D015536:Down-Regulation; D015180:Electrophoresis, Gel, Two-Dimensional; D004789:Enzyme Activation / Q000502:physiology; D054769:G-Protein-Coupled Receptor Kinase 2; D006801:Humans; D047468:Immunoprecipitation; D008264:Macrophages / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051552:beta-Adrenergic Receptor Kinases / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D014409:Tumor Necrosis Factor-alpha; C496567:GRK2 protein, human; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D048051:p38 Mitogen-Activated Protein Kinases