HGF-induced formation of the MET–AXL–ELMO2–DOCK180 complex promotes RAC1 activation, receptor clustering, and cancer cell migration and invasion

• Published in: The Journal of biological chemistry 2018-10, Vol.293 (40), p.15397-15418
• Main Authors: Li, Wenjing, Xiong, Xiahui, Abdalla, Amro, Alejo, Salvador, Zhu, Linyu, Lu, Fei, Sun, Hong
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Axl Receptor Tyrosine Kinase; cancer; cell invasion; Cell Line, Tumor; Cell Membrane - chemistry; Cell Membrane - drug effects; Cell Membrane - metabolism; cell migration; Cell Movement - drug effects; Cell Proliferation - drug effects; cell signaling; Cytoskeletal Proteins - antagonists & inhibitors; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Gene Expression Regulation, Neoplastic; glioblastoma; guanine nucleotide exchange factor (GEF); Hepatocyte Growth Factor - pharmacology; Humans; Neoplasm Invasiveness; Neuroglia - drug effects; Neuroglia - metabolism; Neuroglia - pathology; Protein Transport - drug effects; Proto-Oncogene Mas; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; rac GTP-Binding Proteins - antagonists & inhibitors; rac GTP-Binding Proteins - genetics; rac GTP-Binding Proteins - metabolism; rac1 GTP-Binding Protein - agonists; rac1 GTP-Binding Protein - antagonists & inhibitors; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Ras-related C3 botulinum toxin substrate 1 (Rac1); Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; receptor tyrosine kinase; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA118.003063

The MET proto-oncogene–encoded receptor tyrosine kinase (MET) and AXL receptor tyrosine kinase (AXL) are independently operating receptor tyrosine kinases (RTKs) that are functionally associated with aggressive and invasive cancer cell growth. However, how MET and AXL regulate the migratory properties of cancer cells remains largely unclear. We report here that the addition of hepatocyte growth factor (HGF), the natural ligand of MET, to serum-starved human glioblastoma cells induces the rapid activation of both MET and AXL and formation of highly polarized MET–AXL clusters on the plasma membrane. HGF also promoted the formation of the MET and AXL protein complexes and phosphorylation of AXL, independent of AXL's ligand, growth arrest–specific 6 (GAS6). The HGF-induced MET–AXL complex stimulated rapid and dynamic cytoskeleton reorganization by activating the small GTPase RAC1, a process requiring both MET and AXL kinase activities. We further found that HGF also promotes the recruitment of ELMO2 and DOCK180, a bipartite guanine nucleotide exchange factor for RAC1, to the MET–AXL complex and thereby stimulates the RAC1-dependent cytoskeleton reorganization. We also demonstrated that the MET–AXL–ELMO2–DOCK180 complex is critical for HGF-induced cell migration and invasion in glioblastoma or other cancer cells. Our findings uncover a critical HGF-dependent signaling pathway that involves the assembly of a large protein complex consisting of MET, AXL, ELMO2, and DOCK180 on the plasma membrane, leading to RAC1-dependent cell migration and invasion in various cancer cells.