Division of Cancer Biology, Institute of Cancer Research, Cancer Research UK Centre Tumour Cell Signalling Unit, London, UK.
J Cell Sci. 2012 Apr 1;125(Pt 7):1814-26. doi: 10.1242/jcs.101444. Epub 2012 Feb 10.
Neural precursor expressed, developmentally down-regulated 9 (NEDD9), a member of the Cas family of signal transduction molecules, is amplified at the genetic level in melanoma, and elevated expression levels have been shown to correlate with melanoma progression and metastasis. NEDD9 interacts with the guanine nucleotide exchange factor DOCK3 to promote Rac activation and the elongated, mesenchymal-type of tumour cell invasion, but the molecular mechanisms through which NEDD9 promotes melanoma metastasis are not fully understood. We show that signalling through increased NEDD9 levels requires integrin β3 signalling, which leads to elevated phosphorylation of integrin β3. This results in increased Src and FAK but decreased ROCK signalling to drive elongated, mesenchymal-type invasion in environments that contain vitronectin. NEDD9 overexpression does not affect ROCK signalling through activation of RhoA but decreases ROCKII signalling through Src-dependent phosphorylation of a negative regulatory site Tyr722. In NEDD9-overexpressing melanoma cells, inhibition of Src with dasatinib results in a switch from Rac-driven elongated, mesenchymal-type invasion to ROCK-dependent rounded, amoeboid invasion. These findings brings into question whether dasatinib would work as a therapeutic agent to block melanoma invasion and metastasis. On the basis of the in vitro data presented here, a combination treatment of dasatinib and a ROCK inhibitor might be a better alternative in order to inhibit both elongated, mesenchymal-type and rounded, amoeboid motility.
神经前体细胞表达的发育下调因子 9（NEDD9）是信号转导分子 Cas 家族的成员，在黑色素瘤中存在基因水平扩增，并且表达水平升高与黑色素瘤的进展和转移相关。NEDD9 与鸟嘌呤核苷酸交换因子 DOCK3 相互作用，促进 Rac 的激活和肿瘤细胞的长形、间质型侵袭，但 NEDD9 促进黑色素瘤转移的分子机制尚未完全阐明。我们发现，通过增加 NEDD9 水平的信号需要整合素 β3 信号，这导致整合素 β3 的磷酸化水平升高。这导致Src 和 FAK 的增加，但 ROCK 信号的减少，以在包含 vitronectin 的环境中驱动长形、间质型侵袭。NEDD9 的过表达不会通过激活 RhoA 来影响 ROCK 信号，但会通过Src 依赖性磷酸化负调节位点 Tyr722 来减少 ROCKII 信号。在 NEDD9 过表达的黑色素瘤细胞中，用 dasatinib 抑制Src 会导致从 Rac 驱动的长形、间质型侵袭向 ROCK 依赖性圆形、阿米巴样侵袭的转变。这些发现引发了一个问题，即 dasatinib 是否可以作为一种治疗剂来阻断黑色素瘤的侵袭和转移。基于这里提出的体外数据，dasatinib 和 ROCK 抑制剂的联合治疗可能是一个更好的选择，以抑制长形、间质型和圆形、阿米巴样运动。
