title: Lck/PLCγ control migration and proliferation of interleukin (IL)-2-stimulated T cells via the Rac1 GTPase/glycogen phosphorylase pathway.
abstract: Recently, we have reported that the IL-2-stimulated T cells activate PKCθ in order to phosphorylate the serine residues of αPIX-RhoGEF, and to switch on the Rac1/PYGM pathway resulting in T cell migration and proliferation. However, the molecular mechanism connecting the activated IL-2-R with the PKCθ/αPIX/Rac1/PYGM pathway is still unknown. In this study, the use of a combined pharmacological and genetic approach identified Lck, a Src family member, as the tyrosine kinase phosphorylating PLCγ leading to Rac1 and PYGM activation in the IL-2-stimulated Kit 225 T cells via the PKCθ/αPIX pathway. The PLCγ tyrosine phosphorylation was required to activate first PKCθ, and then αPIX and Rac1/PYGM. The results presented here delineate a novel signalling pathway ranking equally in importance to the three major pathways controlled by the IL-2-R, i.e. PI3K, Ras/MAPK and JAK/STAT pathways. The overall evidence strongly indicates that the central biological role of the novel IL-2-R/Lck/PLCγ/PKCθ/αPIX/Rac1/PYGM signalling pathway is directly related to the control of fundamental cellular processes such as T cell migration and proliferation.
authors: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, 48940 Leioa, Spain; Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Building #205, 48170 Zamudio, Spain.
authors: Francisco
authors: F
authors: Llavero
authors: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, 48940 Leioa, Spain.
authors: Alain
authors: A
authors: Artaso
authors: Three R Labs, Bizkaia Science and Technology Park, Building #103, 48170 Zamudio, Spain.
authors: Hadriano M
authors: HM
authors: Lacerda
authors: Instituto de Patología Experimental, Universidad Nacional de Salta, 4400 Salta, Argentina.
authors: Luis A
authors: LA
authors: Parada
authors: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, 48940 Leioa, Spain; Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Building #205, 48170 Zamudio, Spain; IKERBASQUE, Basque Foundation for Science, Maria Diaz de Haro 3, 48013 Bilbao, Spain. Electronic address: joseluis.zugaza@ehu.es.
authors: José L
authors: JL
authors: Zugaza
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D024981:Glycogen Phosphorylase / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008954:Models, Biological; D051966:Phospholipase C gamma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D064067:Rho Guanine Nucleotide Exchange Factors; D010768:Phosphoserine; D024981:Glycogen Phosphorylase; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; D011493:Protein Kinase C; D051966:Phospholipase C gamma; D020830:rac1 GTP-Binding Protein
keywords: Cell migration and proliferation; Glycogen phosphorylase; Lck; Phosphoserine; Phosphotyrosine; Plc; Rac1