KAI1/CD82 is a metastasis suppressor of solid tumors. The mechanism of KAI1/CD82- mediated metastasis suppression still remains largely elusive. Recent studies indicate that KAI1/CD82 induces the reorganization of membrane microdomains such as lipid rafts and tetraspanin-enriched microdomain (TEM), attenuates growth factor and integrin signaling, and inhibits cell protrusion and retraction. Notably, we also found that KAI1/CD82 suppresses cancer metastasis by inhibiting cancer cell invasiveness. Thus, how KAI1/CD82 inhibits cancer cell movement becomes the outstanding question to understand how KAI1/CD82 suppresses cancer metastasis. We hypothesize that KAI1/CD82 inhibits cancer cell migration and invasion through re-organizing membrane microdomains and consequently reducing protrusive and retraction processes and the outside-in mitogenic signaling. To elucidate how KAI1 suppresses cancer invasion and metastasis, we will first carry out the structural and functional characterization of KAI1/CD82-containing TEM by i) identifying the structural element(s) in CD82 molecule that physically links TEM to lipid rafts, ii) systematically characterizing the protein and lipid components of CD82-positive TEM, and iii) analyze the trafficking and subcellular localization of CD82- containing TEM. Secondly, we will determine the mechanism by which KAI1/CD82-containing TEM regulates the cellular motile activities by addressing how CD82-containing TEM renders membrane curvature and trafficking. We will also assess the roles of CD82-induced alterations in membrane curvature and trafficking in i) membrane motile activities, ii) mitogenic signaling, and iii) CD82-mediated suppression of cancer invasion. Finally, we will determine the mechanism by which KAI1/CD82 inhibits cancer invasion in vivo by addressing i) through which cellular motile activity CD82 suppresses cancer invasion in vivo, ii) the contributions of the proteins physically or functionally associated with CD82 to CD82-mediated suppression of cancer invasion;and iii) whether the CD82 features analyzed above are crucial for its suppression of cancer invasion in vivo. Together, the proposed study will enable us to i) understand how KAI1/CD82 regulates cell migration, cancer invasion, and cancer metastasis as an organizer for membrane microdomains and ii) unveil a novel mechanisms by which cell motility and cancer metastasis are regulated, i.e., membrane curvature and trafficking regulates invasion and metastasis. From the in-depth in vitro and in vivo mechanistic study of KAI1/CD82, we will develop an integrated understanding of cancer invasion and metastasis, which will ultimately lead to the development of KAI1/CD82 into a diagnostic marker and therapeutic target for cancer invasion and metastasis.
Because cancer metastasis is the major cause of the death of cancer patients, understanding how cancer becomes metastatic is crucial for the cancer treatment. In this project, we propose to determine how metastasis suppressor KAI1/CD82 inhibits cancer cell invasion and metastasis at molecular and cellular levels and our proposed studies will provide insight into the general mechanism of cancer metastasis.
|Wei, Quan; Zhang, Feng; Richardson, Mekel M et al. (2014) CD82 restrains pathological angiogenesis by altering lipid raft clustering and CD44 trafficking in endothelial cells. Circulation 130:1493-504|
|Scheffer, Konstanze D; Gawlitza, Alexander; Spoden, Gilles A et al. (2013) Tetraspanin CD151 mediates papillomavirus type 16 endocytosis. J Virol 87:3435-46|
|Peng, Dan; Zuo, Houjuan; Liu, Zhengxiang et al. (2013) The tetraspanin CD151-ARSA mutant inhibits angiogenesis via the YRSL sequence. Mol Med Rep 7:836-42|
|Bari, Rafijul; Guo, Qiusha; Xia, Bing et al. (2011) Tetraspanins regulate the protrusive activities of cell membrane. Biochem Biophys Res Commun 415:619-26|
|He, Bo; Zhang, Yanhui H; Richardson, Mekel M et al. (2011) Differential functions of phospholipid binding and palmitoylation of tumour suppressor EWI2/PGRL. Biochem J 437:399-411|
|Zhang, Feng; Michaelson, Jarett E; Moshiach, Simon et al. (2011) Tetraspanin CD151 maintains vascular stability by balancing the forces of cell adhesion and cytoskeletal tension. Blood 118:4274-84|
|Zhang, Xin A; Mahato, Ram I (2011) Target cell movement in cardiovascular and malignant diseases. Adv Drug Deliv Rev 63:555-7|
|Bari, Rafijul; Zhang, Yanhui H; Zhang, Feng et al. (2009) Transmembrane interactions are needed for KAI1/CD82-mediated suppression of cancer invasion and metastasis. Am J Pathol 174:647-60|
|Xu, Congfeng; Zhang, Yanhui H; Thangavel, Muthusamy et al. (2009) CD82 endocytosis and cholesterol-dependent reorganization of tetraspanin webs and lipid rafts. FASEB J 23:3273-88|
|Zhang, Feng; Kotha, Jayaprakash; Jennings, Lisa K et al. (2009) Tetraspanins and vascular functions. Cardiovasc Res 83:7-15|
Showing the most recent 10 out of 15 publications