The Atypical MAP Kinase ErkB Transmits Distinct Chemotactic Signals through a Core Signaling Module

• Published in: Developmental cell Vol. 48; no. 4; pp. 491 - 505.e9
• Main Authors: Nichols, John M.E., Paschke, Peggy, Peak-Chew, Sew, Williams, Thomas D., Tweedy, Luke, Skehel, Mark, Stephens, Elaine, Chubb, Jonathan R., Kay, Robert R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.02.2019; Cell Press
• Subjects: Animals; Chemotactic Factors - metabolism; chemotaxis; Chemotaxis - physiology; Cyclic AMP - metabolism; Cytoskeleton - metabolism; Dictyostelium - metabolism; Dictyostelium discoideum; MAPK signaling; Mitogen-Activated Protein Kinases - metabolism; phosphoproteomics; Phosphorylation; protein kinase; protein phosphorylation; Receptors, G-Protein-Coupled - metabolism; signal transduction; Signal Transduction - physiology; phosphoproteomics; Dictyostelium discoideum; signal transduction; protein phosphorylation; protein kinase; chemotaxis; MAPK signaling
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2018.12.001

Signaling from chemoattractant receptors activates the cytoskeleton of crawling cells for chemotaxis. We show using phosphoproteomics that different chemoattractants cause phosphorylation of the same core set of around 80 proteins in Dictyostelium cells. Strikingly, the majority of these are phosphorylated at an [S/T]PR motif by the atypical MAP kinase ErkB. Unlike most chemotactic responses, ErkB phosphorylations are persistent and do not adapt to sustained stimulation with chemoattractant. ErkB integrates dynamic autophosphorylation with chemotactic signaling through G-protein-coupled receptors. Downstream, our phosphoproteomics data define a broad panel of regulators of chemotaxis. Surprisingly, targets are almost exclusively other signaling proteins, rather than cytoskeletal components, revealing ErkB as a regulator of regulators rather than acting directly on the motility machinery. ErkB null cells migrate slowly and orientate poorly over broad dynamic ranges of chemoattractant. Our data indicate a central role for ErkB and its substrates in directing chemotaxis. [Display omitted] •Multiple chemoattractants trigger phosphorylation of a core set of proteins•Most core proteins are phosphorylated by ErkB at a p[S/T]PR motif•ErkB targets are almost all signaling proteins, not cytoskeletal effectors•ErkB substrates identify regulators of chemotaxis and motility Signaling via chemoattractant receptors activates the cytoskeleton to drive chemotaxis. Nichols, Paschke et al. show that in Dictyostelium cells, the atypical MAP kinase ErkB mediates the response to multiple chemoattractants by directly phosphorylating a core set of signaling proteins. Mutants in ErkB and its substrates impair chemotaxis and motility.