Directed migration is essential for cell motility in many processes, including development and cancer cell invasion. RSKs (p90 ribosomal S6 kinases) have emerged as central regulators of cell migration; however, the mechanisms mediating RSK-dependent motility remain incompletely understood. We have identified a unique signaling mechanism by which RSK2 promotes cell motility through leukemia-associated RhoGEF (LARG)-dependent Rho GTPase activation. RSK2 directly interacts with LARG and nucleotide-bound Rho isoforms, but not Rac1 or Cdc42. We further show that epidermal growth factor or FBS stimulation induces association of endogenous RSK2 with LARG and LARG with RhoA. In response to these stimuli, RSK2 phosphorylates LARG at Ser1288 and thereby activates RhoA. Phosphorylation of RSK2 at threonine 577 is essential for activation of LARG-RhoA. Moreover, RSK2-mediated motility signaling depends on RhoA and -B, but not RhoC. These results establish a unique RSK2-dependent LARG-RhoA signaling module as a central organizer of directed cell migration and invasion.

中文翻译：

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RSK2通过LARG的丝氨酸磷酸化和Rho GTPases的激活来驱动细胞运动。

定向迁移对于许多过程中的细胞运动至关重要，包括发育和癌细胞侵袭。RSK（p90核糖体S6激酶）已成为细胞迁移的主要调节剂。但是，调解RSK依赖的动力的机制仍不完全了解。我们已经确定了独特的信号传导机制，通过该机制，RSK2通过与白血病相关的RhoGEF（LARG）依赖的Rho GTPase激活来促进细胞运动。RSK2直接与LARG和核苷酸结合的Rho同工型相互作用，但不与Rac1或Cdc42相互作用。我们进一步表明，表皮生长因子或FBS刺激诱导内源性RSK2与LARG和LARG与RhoA的关联。响应于这些刺激，RSK2使Ser1288处的LARG磷酸化，从而激活RhoA。苏氨酸577上RSK2的磷酸化对于激活LARG-RhoA是必不可少的。此外，RSK2介导的运动信号依赖于RhoA和-B，但不依赖RhoC。这些结果建立了独特的依赖RSK2的LARG-RhoA信号传导模块，作为定向细胞迁移和侵袭的中央组织者。