title: PLEKHG2 promotes heterotrimeric G protein βγ-stimulated lymphocyte migration via Rac and Cdc42 activation and actin polymerization.
abstract: PLEKHG2 is a Dbl family Rho guanine nucleotide exchange factor (RhoGEF) whose gene was originally identified as being upregulated in a leukemia mouse model and was later shown to be activated by heterotrimeric G protein βγ (Gβγ) subunits. However, its function and activation mechanisms remain elusive. Here we show that, compared to its expression in primary human T cells, its expression is upregulated in several leukemia cell lines, including Jurkat T cells. Downregulation of PLEKHG2 in Jurkat T cells by small interfering RNAs (siRNAs) specifically inhibited Gβγ-stimulated Rac and Cdc42, but not RhoA, activation. Consequently, suppressing PLEKHG2 expression blocked actin polymerization and SDF1α-stimulated lymphocyte migration. Additional studies indicate that Gβγ likely activates PLEKHG2, in part by binding the N terminus of PLEKHG2 to release an autoinhibition imposed by its C terminus, which interacts with a region encompassing the catalytic Dbl homology (DH) domain. As a result, overexpressing either the N terminus or the C terminus of PLEKHG2 blocked Gβγ-stimulated Rac and Cdc42 activation and prevented Jurkat T cells from forming membrane protrusions and migrating. Together, our studies have provided the first evidence for the endogenous function of PLEKHG2, which may serve as a key Gβγ-stimulated RhoGEF that regulates lymphocyte chemotaxis via Rac and Cdc42 activation and actin polymerization.
authors.affiliation: Departments of Pharmacology.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Runne
authors.forename: Songhai
authors.initials: S
authors.lastname: Chen
mesh_terms: D000199:Actins / Q000378:metabolism; D019943:Amino Acid Substitution; D001665:Binding Sites; D054377:Chemokine CXCL12 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D004789:Enzyme Activation; D044387:GTP-Binding Protein beta Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000502:physiology*; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells / Q000502:physiology*; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000199:Actins; D054377:Chemokine CXCL12; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D020662:Guanine Nucleotide Exchange Factors; C527535:PLEKHG2 protein, human; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins