Functional analysis of HGF/MET signaling and aberrant HGF-activator expression in diffuse large B-cell lymphoma.

Abstract

Inappropriate activation of MET, the receptor tyrosine kinase for hepatocyte growth factor (HGF), has been implicated in tumorigenesis. Although we have previously shown that HGF/MET signaling controls survival and proliferation of multiple myeloma (MM), its role in the pathogenesis of other B-cell malignancies has remained largely unexplored. Here, we have examined a panel of 110 B-cell malignancies for MET expression, which, apart from MM (48%), was found to be largely confined to diffuse large B-cell lymphomas (DLBCLs) (30%). No amplification of the MET gene was found; however, mutational analysis revealed 2 germ-line missense mutations: R1166Q in the tyrosine kinase domain in 1 patient, and R988C in the juxtamembrane domain in 4 patients. The R988C mutation has recently been shown to enhance tumorigenesis. In MET-positive DLBCL cells, HGF induces MEK-dependent activation of ERK and PI3K-dependent phosphorylation of PKB, GSK3, and FOXO3a. Furthermore, HGF induces PI3K-dependent alpha4beta1 integrin-mediated adhesion to VCAM-1 and fibronectin. Within the tumor microenvironment of DLBCL, HGF is provided by macrophages, whereas DLBCL cells themselves produce the serine protease HGF activator (HGFA), which autocatalyzes HGF activation. Taken together, these data indicate that HGF/MET signaling, and secretion of HGFA by DLBCL cells, contributes to lymphomagenesis in DLBCL.

• Authors: Esther P M Tjin, Richard W J Groen, Irma Vogelzang, Patrick W B Derksen, Melanie D Klok, Helen P Meijer, Susanne van Eeden, Steven T Pals, Marcel Spaargaren
• Journal: Blood (Blood) Vol. 107 Issue 2 Pg. 760-8 (Jan 15 2006) ISSN: 0006-4971 [Print] United States
• PMID: 16189274 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FOXO3 protein, human
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• Proto-Oncogene Proteins
• RNA Probes
• RNA, Messenger
• Receptors, Growth Factor
• Hepatocyte Growth Factor
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• MET protein, human
• Proto-Oncogene Proteins c-met
• 3-Phosphoinositide-Dependent Protein Kinases
• Protein Serine-Threonine Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Glycogen Synthase Kinase 3
• MAP Kinase Kinase 1
• MAP2K1 protein, human
• HGF activator
• Serine Endopeptidases

Topics

• 3-Phosphoinositide-Dependent Protein Kinases
• Cell Adhesion
• Class I Phosphatidylinositol 3-Kinases
• Forkhead Box Protein O3
• Forkhead Transcription Factors (metabolism)
• Germ-Line Mutation
• Glycogen Synthase Kinase 3 (metabolism)
• Hepatocyte Growth Factor (genetics, metabolism)
• Humans
• In Situ Hybridization
• Lymphoma, B-Cell (genetics, metabolism)
• Lymphoma, Large B-Cell, Diffuse (genetics, metabolism)
• MAP Kinase Kinase 1 (metabolism)
• Macrophages
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Multiple Myeloma (genetics, metabolism)
• Mutation, Missense
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Polymerase Chain Reaction
• Polymorphism, Single-Stranded Conformational
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-met
• RNA Probes
• RNA, Messenger
• Receptors, Growth Factor (metabolism)
• Serine Endopeptidases (metabolism)
• Signal Transduction
• Tumor Cells, Cultured