新研究揭示一种脂质转化酶如何有助于牵引和移动癌细胞。在该图片中，Rab偶联蛋白(绿色)聚集在浸润性肿瘤细胞的伪足尖端，图片来自Elena Rainero。
转移性癌细胞(metastasizing cancer cell)经常表达提供较好牵引的整合素(integrin)。2012年1月23日发表在The Journal of Cell Biology期刊上的一项新研究揭示一种脂质转化酶帮助这些细胞移动这些整合素。
粘合性整合素蛋白在细胞表面持续性来回循环。携带肿瘤抑制基因p53突变形式的浸润性癌细胞(invasive cancer cell)经常偏离这种过程，增加一种特定整合素的再循环，而在肿瘤中发现的这种整合素提供更加好地握住纤连蛋白纤维(fibronectin fiber)的能力。突变的p53需要Rab偶联蛋白(Rab-coupling protein, RCP)实现这种转变，因为RCP将整合素和促进细胞膜再循环的Rab GTP酶(Rab GTPase)连接起来。接着，RCP与一种称作磷脂酸(phosphatidic acid)的脂质结合在一起。
Jim Norman领导的一个研究小组发现一种制造磷脂酸的酶，即二酰基甘油激酶α(diacylglycerol kinase alpha, DGK-α)，帮助癌细胞移动起来。缺乏DGK-α的肿瘤细胞不能再循环整合素，也不能渗透进胞外基质。
在转移性肿瘤细胞中，让小泡(vesicles)运动的RCP附着到行进中的肿瘤细胞伪足(pseudopod)尖端上。然而，如果DGK-α缺乏的话，这些小泡很少形成，这就表明小泡附着需要磷脂酸。研究人员发现他们研究的特定肿瘤细胞并不会为了转移而增强DGK-α的水平。相反，研究小组认为在获得p53发生突变之后，DGK-α允许癌细胞移动。通过制造结合到DGK-α的脂质，DGK-α能够让肿瘤细胞附着到含有靠近细胞膜的整合素的小泡，毕竟在细胞膜中，整合素能够很容易再循环。(生物谷：towersimper编译)
doi:10.1083/jcb.201109112
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Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration
Elena Rainero, Patrick T. Caswell, Patricia A.J. Muller, Joan Grindlay, Mary W. McCaffrey, Qifeng Zhang, Michael J.O. Wakelam, Karen H. Vousden, Andrea Graziani, and Jim C. Norman
Inhibition of αvβ3 integrin or expression of oncogenic mutants of p53 promote invasive cell migration by enhancing endosomal recycling of α5β1 integrin under control of the Rab11 effector Rab-coupling protein (RCP). In this paper, we show that diacylglycerol kinase α (DGK-α), which phosphorylates diacylglycerol to phosphatidic acid (PA), was required for RCP to be mobilized to and tethered at the tips of invasive pseudopods and to allow RCP-dependent α5β1 recycling and the resulting invasiveness of tumor cells. Expression of a constitutive-active mutant of DGK-α drove RCP-dependent invasion in the absence of mutant p53 expression or αvβ3 inhibition, and conversely, an RCP mutant lacking the PA-binding C2 domain was not capable of being tethered at pseudopod tips. These data demonstrate that generation of PA downstream of DGK-α is essential to connect expression of mutant p53s or inhibition of αvβ3 to RCP and for this Rab11 effector to drive the trafficking of α5β1 that is required for tumor cell invasion through three-dimensional matrices.
