HGF-induced Formation of the MET–AXL–ELMO2–DOCK180 Complex Promotes RAC1 Activation, Receptor Clustering, and Cancer Cell Migration and Invasion

Authors

• Wenjing Li, University of Nevada, Las Vegas; Peking University Shenzhen Graduate School
• Xiahui Xiong, University of Nevada, Las Vegas
• Amro Abdalla, University of Nevada, Las Vegas
• Salvador Alejo, University of Nevada, Las Vegas
• Linyu Zhu, University of Nevada, Las Vegas
• Fei Lu, Peking University Shenzhen Graduate School
• Hong Sun, University of Nevada, Las VegasFollow

Document Type

Article

Publication Date

8-14-2018

Publication Title

Journal of Biological Chemistry

Volume

293

Issue

40

First page number:

15397

Last page number:

15418

Abstract

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.

Disciplines

Chemistry

File Format

pdf

File Size

6900 KB

Language

English

Rights

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Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Repository Citation

Li, W., Xiong, X., Abdalla, A., Alejo, S., Zhu, L., Lu, F., Sun, H. (2018). HGF-induced Formation of the MET–AXL–ELMO2–DOCK180 Complex Promotes RAC1 Activation, Receptor Clustering, and Cancer Cell Migration and Invasion. Journal of Biological Chemistry, 293(40), 15397-15418.
http://dx.doi.org/10.1074/jbc.RA118.003063