TM4SF5 막단백질의 intracellular domain의 기능에 관한 연구

TM4SF5;FAK;p130Cas;ROS

약학대학 약학과 ;

University:서울대학교 대학원

关键词: TM4SF5;    FAK;    p130Cas;    ROS;   

Others  :  http://s-space.snu.ac.kr/bitstream/10371/133432/1/000000003186.pdf

美国|英语

来源: Seoul National University Open Repository

【 摘 要 】

Transmembrane4 L six family member5 (TM4SF5), a branch of the tetraspanin superfamily, is a tetratransmembrane glycoprotein that consists of 197 amino acid. Certain tetraspanins are highly expressed in tumor cells from many types of cancers, whereas TM4SF5 is reported to be over-expressed in hepatocarcinoma. The biological functions of TM4SF5 are predicted to be rendered in tetraspain-enriched microdomains (TERM), although direct evidence has not been previously shown. In previous studies, TM4SF5 is known to cross-talk with integrins and induces EMT (epithelial-mesenchymal transition) at the cellular level, resulting in not only morphological elongation change through actin reorganization, but also promotion of cell migration/invasion and cell proliferation.However, the direct roles of TM4SF5 in intracellular signal transduction remain largely unknown. Here we explored the mechanistic roles of TM4SF5 in intracellular signal transduction. In this study, we have investigated the roles of TM4SF5 intracellular domain by using its deletion mutants of the cytoplasmic regions of TM4SF5 in diverse functions human hepatocarcinoma cells. An interesting aspect in TM4SF5 roles was observed with respect to both its intracellular loop domain and C-terminal domain. At first, we found that the functional blocking anti-integrin β1 antibody and TSAHC inhibitor treatment abolished TM4SF5-enhanced FAK signaling activity. Moreover, we identified that the binding between TM4SF5 intracellular loop domain and FAK was essential for the TM4SF5-mediated FAK activation. Further study of TM4SF5 C-terminal deletion mutant, we observed that TM4SF5 regulates p130Cas signaling activity and ROS generation via its C-terminal domain. In addition, we revealed that the involvement of p130Cas activity which is known to mediate mechanosensing is associated with the differential regulation by TM4SF5 C-terminal domain depending on time and different extracellular environment, in particular, extracellular matrix concentration under cell adhesion-dependent condition. It is of further interest to determine the identification of a role for TM4SF5-mediated p130Cas regulation during mechanosensing and or ROS signaling.Altogether, this study suggests the mechanism of TM4SF5-mediated FAK activation and the mechanosensitive p130Cas activation via the TM4SF5 intracellular domains and partially gives a insight into the role of TM4SF5 in liver cancer.