新研究揭示一種脂質(zhì)轉(zhuǎn)化酶如何有助于牽引和移動癌細胞,。在該圖片中，Rab偶聯(lián)蛋白(綠色)聚集在浸潤性腫瘤細胞的偽足尖端,，圖片來自Elena Rainero,。
轉(zhuǎn)移性癌細胞(metastasizing cancer cell)經(jīng)常表達提供較好牽引的整合素(integrin)。2012年1月23日發(fā)表在The Journal of Cell Biology期刊上的一項新研究揭示一種脂質(zhì)轉(zhuǎn)化酶幫助這些細胞移動這些整合素,。
粘合性整合素蛋白在細胞表面持續(xù)性來回循環(huán),。攜帶腫瘤抑制基因p53突變形式的浸潤性癌細胞(invasive cancer cell)經(jīng)常偏離這種過程，增加一種特定整合素的再循環(huán),，而在腫瘤中發(fā)現(xiàn)的這種整合素提供更加好地握住纖連蛋白纖維(fibronectin fiber)的能力,。突變的p53需要Rab偶聯(lián)蛋白(Rab-coupling protein, RCP)實現(xiàn)這種轉(zhuǎn)變，因為RCP將整合素和促進細胞膜再循環(huán)的Rab GTP酶(Rab GTPase)連接起來,。接著,，RCP與一種稱作磷脂酸(phosphatidic acid)的脂質(zhì)結(jié)合在一起。
Jim Norman領(lǐng)導的一個研究小組發(fā)現(xiàn)一種制造磷脂酸的酶,，即二?；视图っ?alpha;(diacylglycerol kinase alpha, DGK-α)，幫助癌細胞移動起來,。缺乏DGK-α的腫瘤細胞不能再循環(huán)整合素,，也不能滲透進胞外基質(zhì)。
在轉(zhuǎn)移性腫瘤細胞中,，讓小泡(vesicles)運動的RCP附著到行進中的腫瘤細胞偽足(pseudopod)尖端上,。然而，如果DGK-α缺乏的話,，這些小泡很少形成,，這就表明小泡附著需要磷脂酸。研究人員發(fā)現(xiàn)他們研究的特定腫瘤細胞并不會為了轉(zhuǎn)移而增強DGK-α的水平,。相反,，研究小組認為在獲得p53發(fā)生突變之后，DGK-α允許癌細胞移動,。通過制造結(jié)合到DGK-α的脂質(zhì),，DGK-α能夠讓腫瘤細胞附著到含有靠近細胞膜的整合素的小泡，畢竟在細胞膜中,，整合素能夠很容易再循環(huán),。(生物谷：towersimper編譯)
doi:10.1083/jcb.201109112
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PMID:
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.
