title: LAT-independent Erk activation via Bam32-PLC-γ1-Pak1 complexes: GTPase-independent Pak1 activation.
abstract: In T cells, the adaptor Bam32 is coupled to Erk activation downstream of the TCR by an unknown mechanism. We characterized in Jurkat cells and primary T lymphocytes a pathway dependent on Bam32-PLC-γ1-Pak1 complexes, in which Pak1 kinase activates Raf-1 and Mek-1, both upstream of Erk. In the Bam32-PLC-γ1-Pak1 complex, catalytically inactive PLC-γ1 is used as a scaffold linking Bam32 to Pak1. PLC-γ1(C-SH2) directly binds S141 of Bam32, preventing LAT-mediated activation of Ras by PLC-γ1. The Bam32-PLC-γ1 interaction enhances the binding of the SH3 domain of the phospholipase with Pak1. The PLC-γ1(SH3)-Pak1 interaction activates Pak1 independently of the small GTPases Rac1/Cdc42, previously described as being the only activators of Pak1 in T cells. Direct binding of the SH3 domain of PLC-γ1 to Pak1 dissociates inactive Pak1 homodimers, a mechanism required for Pak1 activation. We have thus uncovered a LAT/Ras-independent, Bam32-nucleated pathway that activates Erk signaling in T cells.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Alexandre K
authors.initials: AK
authors.lastname: Rouquette-Jazdanian
authors.forename: Connie L
authors.initials: CL
authors.lastname: Sommers
authors.forename: Robert L
authors.initials: RL
authors.lastname: Kortum
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Morrison
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Samelson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes; D051966:Phospholipase C gamma / Q000378:metabolism; D060066:Protein Interaction Maps; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C110810:LAT protein, human; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C515903:PAK1 protein, human; D019908:Proto-Oncogene Proteins c-raf; D054462:p21-Activated Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D020558:GTP Phosphohydrolases