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|Title:||Activation of EGF receptor endocytosis and ERK1/2 signaling by BPGAP1 requires direct interaction with EEN/endophilin II and a functional RhoGAP domain||Authors:||Lua, B.L.
|Issue Date:||15-Jun-2005||Citation:||Lua, B.L., Low, B.C. (2005-06-15). Activation of EGF receptor endocytosis and ERK1/2 signaling by BPGAP1 requires direct interaction with EEN/endophilin II and a functional RhoGAP domain. Journal of Cell Science 118 (12) : 2707-2721. ScholarBank@NUS Repository. https://doi.org/10.1242/jcs.02383||Abstract:||Rho GTPases are important regulators for cell dynamics. They are activated by guanine nucleotide exchange factors and inactivated by GTPase-activating proteins (GAPs). We recently identified a novel RhoGAP, BPGAP1, that uses the BNIP-2 and Cdc42GAP homology (BCH) domain, RhoGAP domain and proline-rich region to regulate cell morphology and migration. To further explore its roles in intracellular signaling, we employed protein precipitations and matrix-assisted laser desorption/ionization mass-spectrometry and identified EEN/endophilin II as a novel partner of BPGAP1. EEN is a member of the endocytic endophilin family but its function in regulating endocytosis remains unclear. Pull-down and co-immunoprecipitation studies with deletion mutants confirmed that EEN interacted directly with BPGAP1 via its Src homology 3 (SH3) domain binding to the proline-rich region 182-PPPRPPLP-189 of BPGAP1, with prolines 184 and 186 being indispensable for this interaction. Overexpression of EEN or BPGAP1 alone induced EGF-stimulated receptor endocytosis and ERK1/2 phosphorylation. These processes were further enhanced when EEN was present together with the wildtype but not with the non-interactive proline mutant of BPGAP1. However, EEN lacking the SH3 domain served as a dominant negative mutant that completely inhibited these effects. Furthermore, BPGAP1 with a catalytically inactive GAP domain also blocked the effect of EEN and/or BPGAP1 in EGF receptor endocytosis and concomitantly reduced their level of augmentation for ERK1/2 phosphorylation. Our findings reveal a concomitant activation of endocytosis and ERK signaling by BPGAP1 via the coupling of its proline-rich region, which targets EEN and its functional GAP domain. BPGAP1 could therefore provide an important link between cytoskeletal network, endocytic trafficking and Ras/MAPK signaling.||Source Title:||Journal of Cell Science||URI:||http://scholarbank.nus.edu.sg/handle/10635/100001||ISSN:||00219533||DOI:||10.1242/jcs.02383|
|Appears in Collections:||Staff Publications|
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