Ectodomains of the LDL receptor-related proteins LRP1b and LRP4 have anchorage independent functions in vivo.
Ectodomains of the LDL receptor-related proteins LRP1b and LRP4 have anchorage independent functions in vivo.
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DOI：
10.1371/journal.pone.0009960
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发表时间：
2010-04-07
期刊：
影响因子：
3.7
通讯作者：
Adams DJ
中科院分区：
文献类型：
--
作者：
Dietrich MF;van der Weyden L;Prosser HM;Bradley A;Herz J;Adams DJ
低密度脂蛋白（LDL）受体基因家族是一组高度保守的膜受体，在发育过程、脂蛋白运输和细胞信号传导中具有不同的功能。据报道，低密度脂蛋白（LDL）受体相关蛋白1b（LRP 1B）在几种类型的人类恶性肿瘤（包括非小细胞肺癌）中缺失。我们的小组以前曾报道，小鼠Lrp 1b的远端细胞外截短，预计分泌整个完整的细胞外结构域（ECD）是完全可行的，没有明显的表型。在这里，我们已经使用了基因靶向的方法来创建两个小鼠线携带内部重排的外显子Lrp 1b，预计截断蛋白质更接近N-末端，并防止通过分泌途径的正常贩运。这两种突变都导致早期胚胎死亡，但是，正如Lrp 1b在体内的有限表达模式所预期的那样，Lrp 1b的缺失不会导致细胞死亡，因为纯合的Lrp 1b缺陷型囊胚可以在培养中正常繁殖。这与另一个LDL受体家族成员Lrp 4的发现相似。我们提供的体外证据表明，Lrp 4通过金属蛋白酶和γ-分泌酶切割进行调节的膜内加工。我们进一步证明了可溶性胞外结构域对Wnt信号通路的负调控。我们的研究结果强调了Lrp 1b在发育中的关键作用。在小鼠中表达具有跨膜和胞内结构域缺失的Lrp 1b和Lrp 4的截短等位基因导致胞外结构域释放到胞外空间中，这足以赋予活力。相反，无效突变是胚胎（Lrp 1b）或围产期（Lrp 4）致死的。这些发现表明，这两种蛋白质的胞外结构域可能作为细胞外空间中信号配体或信号调节剂的清道夫，从而保留对胚胎发育至关重要的信号阈值，以及LRP 1b在癌症中的明确但知之甚少的作用。
The low-density lipoprotein (LDL) receptor gene family is a highly conserved group of membrane receptors with diverse functions in developmental processes, lipoprotein trafficking, and cell signaling. The low-density lipoprotein (LDL) receptor-related protein 1b (LRP1B) was reported to be deleted in several types of human malignancies, including non-small cell lung cancer. Our group has previously reported that a distal extracellular truncation of murine Lrp1b that is predicted to secrete the entire intact extracellular domain (ECD) is fully viable with no apparent phenotype. Here, we have used a gene targeting approach to create two mouse lines carrying internally rearranged exons of Lrp1b that are predicted to truncate the protein closer to the N-terminus and to prevent normal trafficking through the secretary pathway. Both mutations result in early embryonic lethality, but, as expected from the restricted expression pattern of LRP1b in vivo, loss of Lrp1b does not cause cellular lethality as homozygous Lrp1b-deficient blastocysts can be propagated normally in culture. This is similar to findings for another LDL receptor family member, Lrp4. We provide in vitro evidence that Lrp4 undergoes regulated intramembraneous processing through metalloproteases and γ-secretase cleavage. We further demonstrate negative regulation of the Wnt signaling pathway by the soluble extracellular domain. Our results underline a crucial role for Lrp1b in development. The expression in mice of truncated alleles of Lrp1b and Lrp4 with deletions of the transmembrane and intracellular domains leads to release of the extracellular domain into the extracellular space, which is sufficient to confer viability. In contrast, null mutations are embryonically (Lrp1b) or perinatally (Lrp4) lethal. These findings suggest that the extracellular domains of both proteins may function as a scavenger for signaling ligands or signal modulators in the extracellular space, thereby preserving signaling thresholds that are critical for embryonic development, as well as for the clear, but poorly understood role of LRP1b in cancer.
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影响因子：
64.8
作者：
Glinka, A;Wu, W;Niehrs, C
通讯作者：
Niehrs, C
影响因子：
5.3
作者：
Marschang, P;Brich, J;Herz, J
通讯作者：
Herz, J
影响因子：
11.4
作者：
Rahmatpanah, F. B.;Carstens, S.;Caldwell, C. W.
通讯作者：
Caldwell, C. W.
影响因子：
4.6
作者：
Weatherbee, Scott D.;Anderson, Kathryn V.;Niswander, Lee A.
通讯作者：
Niswander, Lee A.
DOI：
10.1161/01.atv.0000133607.80554.09
发表时间：
2004-08-01
影响因子：
8.7
作者：
Tanaga, K;Bujo, H;Saito, Y
通讯作者：
Saito, Y