| First Author | Hatziapostolou M | Year | 2011 |
| Journal | Sci Signal | Volume | 4 |
| Issue | 187 | Pages | ra55 |
| PubMed ID | 21868363 | Mgi Jnum | J:260389 |
| Mgi Id | MGI:6140285 | Doi | 10.1126/scisignal.2002006 |
| Citation | Hatziapostolou M, et al. (2011) Tumor progression locus 2 mediates signal-induced increases in cytoplasmic calcium and cell migration. Sci Signal 4(187):ra55 |
| abstractText | 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 Galpha(i2)-transduced GPCR signals. Activated Tpl2 promoted the phosphorylation and activation of phospholipase C-beta3 (PLCbeta(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 Galpha(i); from Wnt5a; and from the interleukin-1beta (IL-1beta) 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. |
