BRAF在多种癌症类型中常发生突变，并促进肿瘤发生和转移。作为RAS信号通路中的一个重要开关，BRAF通常能够激活MEK和ERK，并且其突变明显促进转移。然而，BRAF是否能以不同方式刺激转移仍然不明确。在本研究中，我们发现一部分BRAF蛋白质定位在细胞质膜上，并且BRAFV600E突变导致丰富的纤毛状突起形成，这是侵袭性癌细胞的标志。在机制上，BRAF与假足形成相关蛋白VASP发生物理相互作用，并且BRAF特异性催化VASP在Ser157位点的磷酸化。VASP耗竭或Ser157磷酸化的破坏优先减少了携带癌基因BRAF或KRAS的肿瘤细胞的活动能力、侵袭性和转移能力。此外，在临床肿瘤组织中，BRAFV600E与浸润程度呈正相关，表达BRAFV600E的组织显示出VASP Ser157磷酸化水平升高。因此，我们的研究揭示了一个非经典机制，解释了癌基因BRAF或KRAS如何促进转移，表明VASP Ser157磷酸化可能是BRAF或KRAS突变癌症的有价值的治疗靶点。 © 2023. 作者授予Springer Nature Limited独家许可。

BRAF is frequently mutated in various cancer types and contributes to tumorigenesis and metastasis. As an important switch in RAS signaling pathway, BRAF typically enables the activation of MEK and ERK, and its mutation significantly promotes metastasis. However, whether BRAF could stimulate metastasis via a distinct manner is still unknown. Herein, we found that a portion of the BRAF protein localized at the plasma membrane and that the BRAFV600E mutation led to abundant formation of filopodia, which is a hallmark of invasive cancer cells. Mechanistically, BRAF physically interacts with the pseudopod formation-related protein Vasodilator-stimulated phosphoprotein (VASP), and BRAF specifically catalyzes VASP phosphorylation at Ser157. VASP depletion or disruption of Ser157 phosphorylation preferentially reduced the motility, invasion and metastasis of tumor cells harboring oncogenic BRAF or KRAS. Moreover, in clinical cancer tissues, BRAFV600E was positively correlated with the extent of invasion, and tissues with BRAFV600E expression exhibited elevated levels of VASP Ser157 phosphorylation. Our study therefor reveals a noncanonical mechanism by which oncogenic BRAF or KRAS promotes metastasis, suggests that VASP Ser157 phosphorylation might serve as a valuable therapeutic target in BRAF or KRAS mutant cancers.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.