Apparently, UVC irradiation– and hyperosmotic stress–induced cell size and volume changes activate
Src and FAK signaling events that can determine cell survival.
39,40 Phosphorylations of FAK and paxillin can be elicited in cultured cells by cyclical mechanical strain, and FAK couples integrins and cytoskeletal proteins to multiple signaling pathways. In addition, several lines of evidence suggest that FAK is required for stress stimulation to activate MAP kinase pathways including the JNK cascades.
41–45 These studies suggest that stress-induced cellular changes including cell shrinkage may play key roles in the early event in the initiation of FAK and
Src activation, and cytoskeleton remodeling. Ultraviolet C irradiation–induced cell volume changes triggered activation of the FAK-dependent integrin signaling and cytoskeleton reorganization, critically determining UVC irradiation–induced early response in corneal epithelial cells. Previous studies show that UVC irradiation–induced hyperactivity of Kv channels in these cells,
7,11 blockade of KV channels with various Kv channel blockers in UVC-exposed cells significantly suppressed UVC irradiation–induced cell volume change, FAK/
Src activation, and cytoskeleton remodeling. Thus, a linkage between UVC irradiation–induced cell volume alteration due to loss of intracellular K
+ ions and activation of the FAK-dependent integrin pathway can be established in corneal epithelial cells. It also helps to explain the observation of cytoskeleton reorganization in response to UVC stress. Both scaffold kinases FAK and
Src are important integrin receptor-linked tyrosine kinases to elicit cytoskeleton reorganization in many cell types. Our data using PP2 to suppress
Src kinase activity is consistent with other lab's results that
Src is responsible for further phosphorylation of FAK at different tyrosine sites after the site of Y397 is phosphorylated in these cells.
46 We found that K
+ channel blocker, 4-AP, effectively suppressed UVC irradiation–induced increases in FAK and
Src phosphorylation or activation at micromolar levels, indicating that activations of FAK and
Src are downstream events resulted from UVC irradiation–induced K
+ channel hyperactivity and cell shrinkage because their activities were altered by suppression of Kv channels in UVC irradiation–induced cells. We believe that the connection between UVC irradiation–induced activation of Kv channel and scaffold protein kinase in stress-evoked pathways plays important roles in determining corneal epithelial function and fate.