RSK2 signals through stathmin to promote microtubule dynamics and tumor metastasis.
RSK2 signals through stathmin to promote microtubule dynamics and tumor metastasis.
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作者：
Alesi GN;Jin L;Li D;Magliocca KR;Kang Y;Chen ZG;Shin DM;Khuri FR;Kang S
转移是造成>90%的癌症相关死亡的原因。癌细胞中的复杂信号传导协调了从原发性癌症到转移性癌症的进展。然而，这些细胞变化的机制仍然难以捉摸。我们以前证明，p90核糖体S6激酶2（RSK 2）促进肿瘤转移。在此，我们研究了RSK 2在微管动力学调节中的作用及其在癌细胞侵袭和肿瘤转移中的潜在意义。在转移性人类癌细胞中，RSK 2的稳定敲除破坏了微管稳定性，并降低了微管不稳定蛋白stathmin在丝氨酸16处的磷酸化。我们发现RSK 2直接结合并磷酸化癌细胞前沿的stathmin。RSK 2对stathmin的磷酸化减少了stathmin介导的微管解聚。此外，过表达磷酸模拟突变stathmin S16 D显着挽救了降低的侵袭和转移潜力介导的RSK 2敲低在体外和体内。此外，在原发性患者肿瘤样品中，stathmin磷酸化与RSK 2表达和转移性癌症进展正相关。我们的发现表明，RSK 2直接磷酸化stathmin并调节微管聚合，为癌细胞提供促侵袭和促转移优势。因此，RSK 2-stathmin途径代表了转移性人类癌症的有希望的治疗靶点和预后标志物。
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.