Regulatory roles of conserved phosphorylation sites in the activation T-loop of the MAP kinase ERK1

Molecular Biology of the Cell
Shenshen Lai, S L Pelech

Abstract

The catalytic domains of most eukaryotic protein kinases are highly conserved in their primary structures. Their phosphorylation within the well-known activation T-loop, a variable region between protein kinase catalytic subdomains VII and VIII, is a common mechanism for stimulation of their phosphotransferase activities. Extracellular signal-regulated kinase 1 (ERK1), a member of the extensively studied mitogen-activated protein kinase (MAPK) family, serves as a paradigm for regulation of protein kinases in signaling modules. In addition to the well-documented T202 and Y204 stimulatory phosphorylation sites in the activation T-loop of ERK1 and its closest relative, ERK2, three additional flanking phosphosites have been confirmed (T198, T207, and Y210 from ERK1) by high-throughput mass spectrometry. In vitro kinase assays revealed the functional importance of T207 and Y210, but not T198, in negatively regulating ERK1 catalytic activity. The Y210 site could be important for proper conformational arrangement of the active site, and a Y210F mutant could not be recognized by MEK1 for phosphorylation of T202 and Y204 in vitro. Autophosphorylation of T207 reduces the catalytic activity and stability of activated ERK1. We propose that...Continue Reading

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Citations

Oct 13, 2016·Molecular BioSystems·Daniel Ian McSkimmingNatarajan Kannan
Feb 7, 2012·Biochimica Et Biophysica Acta·Caroline C PhilpottAvery G Frey
Jun 14, 2019·Monoclonal Antibodies in Immunodiagnosis and Immunotherapy·Andrey VelichkovVelislava Terzieva
Mar 27, 2019·Evidence-based Complementary and Alternative Medicine : ECAM·Thunwa BinlatehPilaiwanwadee Hutamekalin
Jun 15, 2019·The Biochemical Journal·Yuanya ZhangYingchun Wang
Jun 25, 2020·Nature Reviews. Molecular Cell Biology·Hugo LavoieMarc Therrien
Feb 6, 2017·BMC Bioinformatics·Daniel Ian McSkimmingNatarajan Kannan
Mar 16, 2017·Cell Cycle·Sabine Elowe
Jan 28, 2021·International Journal of Molecular Sciences·Gema González-RubioMaría Molina
May 3, 2021·Cellular Signalling·Michael Mutlak, Izhak Kehat

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Methods Mentioned

BETA
phosphotransferase
affinity purification
dot blot
chip
GTPase
immunoprecipitation
transfection
scraping

Software Mentioned

PhosphoSitePlus
ImaGene

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