title: Ligand-dependent serum response factor activation by the human CC chemokine receptors CCR2a and CCR2b is mediated by G proteins of the Gq family.
abstract: Expression of the human CCR2 receptors, CCR2a and CCR2b, in mammalian cells results in ligand-dependent changes in the activity of multiple cellular signal transduction pathways, mediated in most cases by pertussis toxin-sensitive heterotrimeric G proteins of the Gi/o subfamily. In addition, CCR2a and CCR2b receptors have been shown to couple to Gq family members, triggering the canonical activation of phospholipase Cβ isoenzymes. Activation of pertussis toxin-insensitive Gq proteins by cell-surface receptors is not only coupled to activation of phospholipase isoenzymes but also to Rho guanine nucleotide exchange factors, which in turn mediate activation of the Rho GTPases. Activated Rho GTPases regulate numerous cellular functions, including the organization of the actin cytoskeleton and gene transcription, such as the transcription factor serum response factor. These findings prompted us to investigate whether CCR2a and/or CCR2b stimulate serum response factor activity. The results presented herein demonstrate that stimulation of human CCR2a- or CCR2b-expressing COS-7 cells caused a vigorous induction of serum response factor activity. This effect was specifically mediated by Gq and/or G14, as well as Rho A and/or a closely related Rho GTPase. Furthermore, the stimulatory effect of CCR2a and CCR2b and Gαq was sensitive to coexpression of the Gαq-interacting leukemia-associated Rho guanine nucleotide exchange factor. The findings of the work indicate a role for Gαq and/or Gα14 and in CCR2a/CCR2b-stimulated Rho A GTPase-mediated serum response factor activation and introduce a noncanonical pathway activated by CCR2 receptors by coupling to Gq proteins.
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University, Medical Center, Albert-Einstein-Allee 11, Ulm, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Vatter
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University, Medical Center, Albert-Einstein-Allee 11, Ulm, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schuhholz
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University, Medical Center, Albert-Einstein-Allee 11, Ulm, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Koenig
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University, Medical Center, Albert-Einstein-Allee 11, Ulm, Germany.
authors.forename: Mariana
authors.initials: M
authors.lastname: Pfreimer
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University, Medical Center, Albert-Einstein-Allee 11, Ulm, Germany barbara.moepps@uni-ulm.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Moepps
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D018932:Chemokine CCL2 / Q000494:pharmacology; D002522:Chlorocebus aethiops; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D037342:Pertussis Toxin / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism*; D026362:Serum Response Factor / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D020741:rho GTP-Binding Proteins
chemical_list: D018932:Chemokine CCL2; D008024:Ligands; D020033:Protein Isoforms; D054390:Receptors, CCR2; D026362:Serum Response Factor; D037342:Pertussis Toxin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020741:rho GTP-Binding Proteins
keywords: CCL2; RhoGEF; RhoGTPase; noncanonical signaling