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Tetraspan TM4SF5-dependent direct activation of FAK and metastatic potential of hepatocarcinoma cells
Oisun Jung, Suyong Choi, Sun-Bok Jang, Sin-Ae Lee, Ssang-Taek Lim, Yoon-Ju Choi, Hye-Jin Kim, Do-Hee Kim, Tae Kyoung Kwak, Hyeonjung Kim, Minkyung Kang, Mi-Sook Lee, Sook Young Park, Jihye Ryu, Doyoung Jeong, Hae-Kap Cheong, Hyun Jeong Kim, Ki Hun Park, Bong-Jin Lee, David D. Schlaepfer, Jung Weon Lee


Transmembrane 4 L six family member 5 (TM4SF5) plays an important role in cell migration, and focal adhesion kinase (FAK) activity is essential for homeostatic and pathological migration of adherent cells. However, it is unclear how TM4SF5 signaling mediates the activation of cellular migration machinery, and how FAK is activated during cell adhesion. Here, we showed that direct and adhesion-dependent binding of TM4SF5 to FAK causes a structural alteration that may release the inhibitory intramolecular interaction in FAK. In turn, this may activate FAK at the cell's leading edge, to promote migration/invasion and in vivo metastasis. TM4SF5-mediated FAK activation occurred during integrin-mediated cell adhesion. TM4SF5 was localized at the leading edge of the cells, together with FAK and actin-organizing molecules, indicating a signaling link between TM4SF5/FAK and actin reorganization machinery. Impaired interactions between TM4SF5 and FAK resulted in an attenuated FAK phosphorylation (the signaling link to actin organization machinery) and the metastatic potential. Our findings demonstrate that TM4SF5 directly binds to and activates FAK in an adhesion-dependent manner, to regulate cell migration and invasion, suggesting that TM4SF5 is a promising target in the treatment of metastatic cancer.


  • Funding

    This work was supported by the Korea Healthcare Technology R&D Project, MHWFA, Republic of Korea [grant number A092006 to B.-J.L.];, a grant from High Field NMR Research Program of Korea Basic Science Institute (to B.-J. L.); the National Research Foundation (NRF) by the MEST of Korea for Tumor Microenvironment Global Core Research Center (GCRC) grant, [grant number 2012-0004891]; senior researchers program (Leap research) [grant number 2012-0005606]; and Global Frontier Project grant [grant number NRF-M1AXA002-2011-0028411], and a grant of the Korean Health Technology R&D Project [grant number A100727], MHWFA, Republic of Korea to J.W.L.

  • Supplementary material available online at

  • Accepted September 23, 2012.
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