title: Guanine nucleotide exchange factor αPIX leads to activation of the Rac 1 GTPase/glycogen phosphorylase pathway in interleukin (IL)-2-stimulated T cells.
abstract: Recently, we have reported that the active form of Rac 1 GTPase binds to the glycogen phosphorylase muscle isoform (PYGM) and modulates its enzymatic activity leading to T cell proliferation. In the lymphoid system, Rac 1 and in general other small GTPases of the Rho family participate in the signaling cascades that are activated after engagement of the T cell antigen receptor. However, little is known about the IL-2-dependent Rac 1 activator molecules. For the first time, a signaling pathway leading to the activation of Rac 1/PYGM in response to IL-2-stimulated T cell proliferation is described. More specifically, αPIX, a known guanine nucleotide exchange factor for the small GTPases of the Rho family, preferentially Rac 1, mediates PYGM activation in Kit 225 T cells stimulated with IL-2. Using directed mutagenesis, phosphorylation of αPIX Rho-GEF serines 225 and 488 is required for activation of the Rac 1/PYGM pathway. IL-2-stimulated serine phosphorylation was corroborated in Kit 225 T cells cultures. A parallel pharmacological and genetic approach identified PKCθ as the serine/threonine kinase responsible for αPIX serine phosphorylation. The phosphorylated state of αPIX was required to activate first Rac 1 and subsequently PYGM. These results demonstrate that the IL-2 receptor activation, among other early events, leads to activation of PKCθ. To activate Rac 1 and consequently PYGM, PKCθ phosphorylates αPIX in T cells. The biological significance of this PKCθ/αPIX/Rac 1 GTPase/PYGM signaling pathway seems to be the control of different cellular responses such as migration and proliferation.
authors.affiliation: From the Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, 48940 Leioa, Spain, the Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Building 205, 48170 Zamudio, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Llavero
authors.affiliation: From the Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, 48940 Leioa, Spain.
authors.forename: Bakarne
authors.initials: B
authors.lastname: Urzelai
authors.affiliation: the Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark.
authors.forename: Nerea
authors.initials: N
authors.lastname: Osinalde
authors.affiliation: the Pharmascience Division, Technological Park of Health Sciences, Avda. de la Ciencia, s/n 18100 Armilla, Granada, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gálvez
authors.affiliation: the Department of Biomedical Sciences and Human Oncology, Unit of Cancer Epidemiology, Università degli Studi di Torino, 10124 Torino, Italy.
authors.forename: Hadriano M
authors.initials: HM
authors.lastname: Lacerda
authors.affiliation: the Instituto de Patología Experimental, Universidad Nacional de Salta, 4400 Salta, Argentina, and.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Parada
authors.affiliation: From the Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, 48940 Leioa, Spain, the Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Building 205, 48170 Zamudio, Spain, the IKERBASQUE, Basque Foundation for Science, Maria Diaz de Haro 3, 48013 Bilbao, Spain joseluis.zugaza@ehu.es.
authors.forename: José L
authors.initials: JL
authors.lastname: Zugaza
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D017931:DNA Primers; D004789:Enzyme Activation; D024981:Glycogen Phosphorylase / Q000378:metabolism*; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D064067:Rho Guanine Nucleotide Exchange Factors / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C576603:ARHGEF6 protein, human; D017931:DNA Primers; C107953:RAC1 protein, human; D064067:Rho Guanine Nucleotide Exchange Factors; D018664:Interleukin-12; D024981:Glycogen Phosphorylase; D020830:rac1 GTP-Binding Protein
keywords: Guanine Nucleotide Exchange Factor (GEF); Phosphorylase; Protein Kinase C (PKC); Protein Phosphorylation; Ras-related C3 Botulinum Toxin Substrate 1 (Rac1)