Metastasis is responsible for >90% of
cancer-related deaths. Complex signaling in
cancer cells orchestrates the progression from a primary to a metastatic
cancer. However, the mechanisms of these cellular changes remain elusive. We previously demonstrated that
p90 ribosomal S6 kinase 2 (RSK2) promotes
tumor metastasis. Here we investigated the role of RSK2 in the regulation of microtubule dynamics and its potential implication in
cancer cell invasion and
tumor metastasis. Stable knockdown of RSK2 disrupted microtubule stability and decreased phosphorylation of
stathmin, a microtubule-destabilizing
protein, at
serine 16 in metastatic human
cancer cells. We found that RSK2 directly binds and phosphorylates
stathmin at the leading edge of
cancer cells. Phosphorylation of
stathmin by RSK2 reduced
stathmin-mediated microtubule depolymerization. Moreover, overexpression of phospho-mimetic mutant
stathmin S16D significantly rescued the decreased invasive and metastatic potential mediated by RSK2 knockdown in vitro and in vivo. Furthermore,
stathmin phosphorylation positively correlated with RSK2 expression and metastatic
cancer progression in primary patient
tumor samples. Our finding demonstrates that RSK2 directly phosphorylates
stathmin and regulates microtubule polymerization to provide a pro-invasive and pro-metastatic advantage to
cancer cells. Therefore, the RSK2-stathmin pathway represents a promising therapeutic target and a prognostic marker for metastatic human
cancers.