Regulation of RhoA activation and cell motility by c-Jun N-terminal kinases and Net1.

Jnks are mitogen activated protein kinases that are best known for regulating transcription and apoptotic signaling. However, they also play important roles in controlling cell motility and invasion by phosphorylating many actin and microtubule regulatory proteins. These mechanisms have important implications for normal cell motility as well as cancer metastasis. Jnks are activated by growth factors and cytokines that stimulate cell motility, and this often requires upstream activation of Rho GTPases. Our recent work indicates that Jnks may also regulate Rho GTPase activation. Specifically, we found that Jnk-dependent phosphorylation of the RhoA guanine nucleotide exchange factor (RhoGEF) Net1A promotes its cytosolic accumulation to drive RhoA activation and actin cytoskeletal reorganization. Net1A is unusual among RhoGEFs in that it is sequestered in the nucleus to prevent aberrant RhoA activation. Importantly, Jnk-stimulated cytosolic localization of Net1A is sufficient to stimulate cell motility and extracellular matrix invasion in non-invasive breast cancer cells. Since Net1A expression is critical for cancer cell motility and invasion in vitro, and breast cancer metastasis in vivo, these data uncover a previously unappreciated regulatory mechanism that may contribute to metastasis in multiple types of cancer.