LAT-Independent Erk Activation via Bam32-PLC-γ1-Pak1 Complexes: GTPase-Independent Pak1 Activation

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-gamma 1-Pak1 complexes, in which Pak1 kinase activates Raf-1 and Mek-1, both upstream of Erk. In the Bam32-PLC-gamma 1-Pak1 complex, catalytically inactive PLC-gamma 1 is used as a scaffold linking Bam32 to Pak1. PLC-gamma 1(C-SH2) directly binds S141 of Bam32, preventing LAT-mediated activation of Ras by PLC-gamma 1. The Bam32-PLC-gamma 1 interaction enhances the binding of the SH3 domain of the phospholipase with Pak1. The PLC-gamma 1(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-gamma 1 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.