Faculty Collaboration Database

TrkBT1 induces liver metastasis of pancreatic cancer cells by sequestering Rho GDP dissociation inhibitor and promoting RhoA activation. Cancer Res 2009 Oct 01;69(19):7851-9

Date

09/24/2009

Pubmed ID

19773448

Pubmed Central ID

PMC3087630

DOI

10.1158/0008-5472.CAN-08-4002

Scopus ID

2-s2.0-70350218798 (requires institutional sign-in at Scopus site)   45 Citations

Abstract

Many genetic and molecular alterations, such as K-ras mutation and NF-kappaB activation, have been identified in pancreatic cancer. However, the mechanisms by which pancreatic cancer metastasizes still remain to be determined. Although we previously showed that the tropomyosin-related kinase B (TrkB) was significantly correlated with the development of liver metastasis, its function in pancreatic cancer metastasis remained unresolved. In the present study, we showed that overexpressed TrkB is an alternatively spliced transcript variant of TrkB (TrkBT1) with a unique COOH-terminal 12-amino acid sequence and is mainly localized in the cytoplasm. Our results showed that overexpression of Flag-tagged TrkBT1 but not a Flag-tagged TrkBT1 COOH-terminal deletion mutant (Flag-TrkBT1DeltaC) in nonmetastatic pancreatic cancer cells enhanced cell proliferation, promoted formation of colonies in soft agar, stimulated tumor cell invasion, and induced liver metastasis in an orthotopic xenograft mouse model of pancreatic cancer. TrkBT1 interacted with Rho GDP dissociation inhibitor (GDI) in vivo, but Flag-TrkBT1DeltaC did not. Furthermore, overexpression of Flag-TrkBT1 and knockdown of RhoGDI expression by RhoGDI short hairpin RNAs promoted RhoA activation, but Flag-TrkBT1DeltaC overexpression did not. Therefore, our results showed that TrkBT1 overexpression induces liver metastasis of pancreatic cancer and uncovered a unique signaling mechanism by which TrkBT1 sequesters GDI and activates RhoA signaling.

Author List

Li Z, Chang Z, Chiao LJ, Kang Y, Xia Q, Zhu C, Fleming JB, Evans DB, Chiao PJ

Author

Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cadherins
Cell Adhesion
Cell Growth Processes
Cell Line, Tumor
Enzyme Activation
Female
Guanine Nucleotide Dissociation Inhibitors
Humans
Liver Neoplasms
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Invasiveness
Pancreatic Neoplasms
Protein Subunits
Receptor, trkB
Transplantation, Heterologous
Up-Regulation
rhoA GTP-Binding Protein