title: Noncanonical mode of ERK action controls alternative αβ and γδ T cell lineage fates.
abstract: Gradations in extracellular regulated kinase (ERK) signaling have been implicated in essentially every developmental checkpoint or differentiation process encountered by lymphocytes. Yet, despite intensive effort, the molecular basis by which differences in ERK activation specify alternative cell fates remains poorly understood. We report here that differential ERK signaling controls lymphoid-fate specification through an alternative mode of action. While ERK phosphorylates most substrates, such as RSK, by targeting them through its D-domain, this well-studied mode of ERK action was dispensable for development of γδ T cells. Instead, development of γδ T cells was dependent upon an alternative mode of action mediated by the DEF-binding pocket (DBP) of ERK. This domain enabled ERK to bind a distinct and select set of proteins required for specification of the γδ fate. These data provide the first in vivo demonstration for the role of DBP-mediated interactions in orchestrating alternate ERK-dependent developmental outcomes.
authors.affiliation: Blood Cell Development and Cancer Keystone, Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
authors.forename: Sang-Yun
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Blood Cell Development and Cancer Keystone, Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Coffey
authors.affiliation: Blood Cell Development and Cancer Keystone, Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Fahl
authors.affiliation: Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
authors.forename: Suraj
authors.initials: S
authors.lastname: Peri
authors.affiliation: Blood Cell Development and Cancer Keystone, Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Rhodes
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, 333 Cottman Avenue, Philadelphia, PA19111-2497, USA.
authors.forename: Kathy Q
authors.initials: KQ
authors.lastname: Cai
authors.affiliation: Rosetta Inpharmatics LLC, 12040 115th Avenue NE, Suite 210 Kirkland, WA 98034, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Carleton
authors.affiliation: Department of Cellular and Molecular Medicine and Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hedrick
authors.affiliation: Institute of Immunology, University Clinics Ulm, 89081, Germany.
authors.forename: Hans Joerg
authors.initials: HJ
authors.lastname: Fehling
authors.affiliation: Sunnybrook Research Institute, and the Department of Immunology, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Zúñiga-Pflücker
authors.affiliation: Blood Cell Development and Cancer Keystone, Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
authors.forename: Dietmar J
authors.initials: DJ
authors.lastname: Kappes
authors.affiliation: Blood Cell Development and Cancer Keystone, Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA. Electronic address: david.wiest@fccc.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Wiest
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D055550:Protein Stability; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013379:Substrate Specificity / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D048049:Extracellular Signal-Regulated MAP Kinases