Date of Award
Doctor of Philosophy (PhD)
Xin Zhang, Ph.D.
Lisa K. Jennings, Ph.D. Ken Nishimoto, Ph.D. Rennolds S. Ostrom, Ph.D. Radhakrishna Rao, Ph.D.
KAI1/CD82, tetraspanins, actin, lamellipodia, Rac, and Rho
To determine how tetraspanin KAI1/CD82, a tumor metastasis suppressor, inhibits cell migration, we assessed which motility-related cellular events are altered by KAI1/CD82 and how KAI1/CD82 regulates these events. We found that KAI1/CD82-overexpressing cancer cells exhibit various morphologies but typically display elongated cellular extensions and a lack of lamellipodia. Live imaging demonstrated that the formation of lamellipodia and retraction of extensions were deficient upon KAI1/CD82 overexpression.
The deficiency in developing motility-related cellular events was accompanied by defects in actin cortical network and stress fiber formations. Notably, actin polymerization was attenuated by KAI1/CD82. Although Rac1 activity was diminished upon KAI1/CD82 expression, Rac1 could not rescue lamellipodia formation because Rac1 activity is not required for this process in Du145 prostate cancer cells. Surprisingly, RhoA activity was upregulated upon KAI1/CD82 overexpression despite the loss of stress fiber and lack of cellular retraction, suggesting that enhanced RhoA activity is a compensatory effect resulting form impaired actin polymerization. Cofilin, an effector of both Rac and Rho, cannot translocate to the cell periphery in KAI1/CD82-overexpressing cells to facilitate lamellipodia formation, though the total and active cofilin proteins remain unchanged.
In summary, we demonstrate that KAI1/CD82 inhibits protrusion and retraction events crucial for cell movement by disrupting actin cortical network and stress fiber formations. At the molecular level, KAI1/CD82 impairs actin polymerization by unbalancing Rac1 and RhoA activities. KAI1/CD82-induced disruption of actin organization likely results from the suppression of common signaling steps of multiple pathways but is alleviated by cell-cell adhesion.
Liu, Wei , "Tetraspanin KAI1/CD82 inhibits cell migration-related cellular events via reorganizing actin network" (2007). Theses and Dissertations (ETD). Paper 155. http://dx.doi.org/10.21007/etd.cghs.2007.0187.