Tumor Progression Locus 2 Mediates Signal-Induced Increases in Cytoplasmic Calcium and Cell Migration

Sci. Signal., 23 August 2011
Vol. 4, Issue 187, p. ra55
DOI: 10.1126/scisignal.2002006

Tumor Progression Locus 2 Mediates Signal-Induced Increases in Cytoplasmic Calcium and Cell Migration

  1. Maria Hatziapostolou,
  2. Georgios Koukos,
  3. Christos Polytarchou,
  4. Filippos Kottakis,
  5. Oksana Serebrennikova,
  6. Athan Kuliopulos, and
  7. Philip N. Tsichlis*
  1. Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
  1. *To whom correspondence should be addressed. E-mail: ptsichlis{at}tuftsmedicalcenter.org


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 Gαi2-transduced GPCR signals. Activated Tpl2 promoted the phosphorylation and activation of phospholipase C–β3 (PLCβ3); consequently, Tpl2 was required for thrombin-dependent production of inositol 1,4,5-trisphosphate (IP3), IP3-mediated cytoplasmic calcium ion (Ca2+) 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 Ca2+ signaling pathways. Pharmacological and genetic studies revealed that stimulation of cell migration by Tpl2 depends on both of these pathways. Tpl2 also promoted Ca2+ signals and cell migration from sphingosine 1-phosphate–responsive GPCRs, which also couple to Gαi; 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 Ca2+ signaling and cell migration.


M. Hatziapostolou, G. Koukos, C. Polytarchou, F. Kottakis, O. Serebrennikova, A. Kuliopulos, and P. N. Tsichlis, Tumor Progression Locus 2 Mediates Signal-Induced Increases in Cytoplasmic Calcium and Cell Migration. Sci. Signal. 4, ra55 (2011).

Tpl2 knockout keratinocytes have increased biomarkers for invasion and metastasis
K. L. DeCicco-Skinner, S. A. Jung, T. Tabib, J. C. Gwilliam, H. Alexander, S. E. Goodheart, A. S. Merchant, M. Shan, C. Garber, J. S. Wiest et al.
Carcinogenesis 34, 2789-2798 (1 December 2013)

Tpl2 Kinase Impacts Tumor Growth and Metastasis of Clear Cell Renal Cell Carcinoma
H. W. Lee, K. M. Joo, J. E. Lim, H. J. Cho, H. J. Cho, M. C. Park, H. J. Seol, S. I. Seo, J.-I. Lee, S. Kim et al.
Mol Cancer Res 11, 1375-1386 (1 November 2013)

Tpl2 kinase regulates Fc{gamma}R signaling and immune thrombocytopenia in mice
I. Kyrmizi, M. Ioannou, M. Hatziapostolou, P. N. Tsichlis, D. T. Boumpas, and I. Tassiulas
J. Leukoc. Biol. 94, 751-757 (1 October 2013)

Noncanonical Matrix Metalloprotease-1-Protease-activated Receptor-1 Signaling Triggers Vascular Smooth Muscle Cell Dedifferentiation and Arterial Stenosis
K. M. Austin, N. Nguyen, G. Javid, L. Covic, and A. Kuliopulos
J Biol Chem 288, 23105-23115 (9 August 2013)

Cot/tpl2-MKK1/2-Erk1/2 controls mTORC1-mediated mRNA translation in Toll-like receptor-activated macrophages
M. Lopez-Pelaez, S. Fumagalli, C. Sanz, C. Herrero, S. Guerra, M. Fernandez, and S. Alemany
Mol. Biol. Cell 23, 2982-2992 (1 August 2012)

Tpl2 ablation promotes intestinal inflammation and tumorigenesis in Apcmin mice by inhibiting IL-10 secretion and regulatory T-cell generation
O. B. Serebrennikova, C. Tsatsanis, C. Mao, E. Gounaris, W. Ren, L. D. Siracusa, A. G. Eliopoulos, K. Khazaie, and P. N. Tsichlis
Proc. Natl. Acad. Sci. USA 109, E1082-E1091 (1 May 2012)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882