title: Tumor progression locus 2 mediates signal-induced increases in cytoplasmic calcium and cell migration.
abstract: The mitogen-activated protein kinase kinase kinase (MAPKKK or MAP3K) tumor progression locus 2 (Tpl2) is required for the transduction of signals initiated by the thrombin-activated G protein-coupled receptor (GPCR) protease-activated receptor-1 (PAR1), which promote reorganization of the actin cytoskeleton and cell migration. Here, we show that Tpl2 is activated through Gα(i2)-transduced GPCR signals. Activated Tpl2 promoted the phosphorylation and activation of phospholipase C-β3 (PLCβ(3)); consequently, Tpl2 was required for thrombin-dependent production of inositol 1,4,5-trisphosphate (IP(3)), IP(3)-mediated cytoplasmic calcium ion (Ca(2+)) signals, and the activation of classical and novel members of the protein kinase C (PKC) family. A PKC-mediated feedback loop facilitated extracellular signal-regulated kinase (ERK) activation in response to Tpl2 and contributed to the coordinate regulation of the ERK and Ca(2+) signaling pathways. Pharmacological and genetic studies revealed that stimulation of cell migration by Tpl2 depends on both of these pathways. Tpl2 also promoted Ca(2+) signals and cell migration from sphingosine 1-phosphate-responsive GPCRs, which also couple to Gα(i); from Wnt5a; and from the interleukin-1β (IL-1β) receptor, a member of the Toll-IL-1R (TIR) domain family. Our data provide new insights into the role of Tpl2 in GPCR-mediated Ca(2+) signaling and cell migration.
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Hatziapostolou
authors.forename: Georgios
authors.initials: G
authors.lastname: Koukos
authors.forename: Christos
authors.initials: C
authors.lastname: Polytarchou
authors.forename: Filippos
authors.initials: F
authors.lastname: Kottakis
authors.forename: Oksana
authors.initials: O
authors.lastname: Serebrennikova
authors.forename: Athan
authors.initials: A
authors.lastname: Kuliopulos
authors.forename: Philip N
authors.initials: PN
authors.lastname: Tsichlis
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000502:physiology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000071818:Wnt-5a Protein
chemical_list: D011518:Proto-Oncogene Proteins; D044463:Receptor, PAR-1; D017472:Receptors, Interleukin-1; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D051960:GTP-Binding Protein alpha Subunit, Gi2; D002118:Calcium