title: Rac1 protein regulates glycogen phosphorylase activation and controls interleukin (IL)-2-dependent T cell proliferation.
abstract: Small GTPases of the Rho family have been implicated in important cellular processes such as cell migration and adhesion, protein secretion, and/or gene transcription. In the lymphoid system, these GTPases participate in the signaling cascades that are activated after engagement of antigen receptors. However, little is known about the role that Rho GTPases play in IL-2-mediated responses. Here, we show that IL-2 induces Rac1 activation in Kit 225 T cells. We identified by mass spectrometry the muscle isoform of glycogen phosphorylase (PYGM) as a novel Rac1 effector molecule in IL-2-stimulated cells. The interaction between the active form of Rac1 (Rac1-GTP) and PYGM was established directly through a domain comprising amino acids 191-270 of PYGM that exhibits significant homology with the Rac binding domain of PAK1. The integrity of this region was crucial for PYGM activation. Importantly, IL-2-dependent cellular proliferation was inhibited upon blocking both the activation of Rac1 and the activity of PYGM. These results reveal a new role for Rac1 in cell signaling, showing that this GTPase triggers T cell proliferation upon IL-2 stimulation by associating with PYGM and modulating its enzymatic activity.
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, 48940 Leioa, Spain.
authors.forename: Onetsine
authors.initials: O
authors.lastname: Arrizabalaga
authors.forename: Hadriano M
authors.initials: HM
authors.lastname: Lacerda
authors.forename: Ana M
authors.initials: AM
authors.lastname: Zubiaga
authors.forename: José L
authors.initials: JL
authors.lastname: Zugaza
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D049109:Cell Proliferation; D004789:Enzyme Activation; D015870:Gene Expression; D024982:Glycogen Phosphorylase, Muscle Form / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D010449:Peptide Mapping; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism / Q000502:physiology*
chemical_list: C508594:IL2 protein, human; D007376:Interleukin-2; D010446:Peptide Fragments; C107953:RAC1 protein, human; D024982:Glycogen Phosphorylase, Muscle Form; D020830:rac1 GTP-Binding Protein