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Hippo 信号复合物的相分离。

Phase separation of Hippo signalling complexes.

机构信息

EMBL Australia, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.

HHMI Janelia Research Campus, Ashburn, VA, USA.

出版信息

EMBO J. 2023 Mar 15;42(6):e112863. doi: 10.15252/embj.2022112863. Epub 2023 Feb 20.

DOI:10.15252/embj.2022112863
PMID:36807601
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10015380/
Abstract

The Hippo pathway was originally discovered to control tissue growth in Drosophila and includes the Hippo kinase (Hpo; MST1/2 in mammals), scaffold protein Salvador (Sav; SAV1 in mammals) and the Warts kinase (Wts; LATS1/2 in mammals). The Hpo kinase is activated by binding to Crumbs-Expanded (Crb-Ex) and/or Merlin-Kibra (Mer-Kib) proteins at the apical domain of epithelial cells. Here we show that activation of Hpo also involves the formation of supramolecular complexes with properties of a biomolecular condensate, including concentration dependence and sensitivity to starvation, macromolecular crowding, or 1,6-hexanediol treatment. Overexpressing Ex or Kib induces formation of micron-scale Hpo condensates in the cytoplasm, rather than at the apical membrane. Several Hippo pathway components contain unstructured low-complexity domains and purified Hpo-Sav complexes undergo phase separation in vitro. Formation of Hpo condensates is conserved in human cells. We propose that apical Hpo kinase activation occurs in phase separated "signalosomes" induced by clustering of upstream pathway components.

摘要

Hippo 通路最初在果蝇中被发现可控制组织生长，包括 Hippo 激酶（Hpo；哺乳动物中的 MST1/2）、支架蛋白 Salvador（Sav；哺乳动物中的 SAV1）和 Warts 激酶（Wts；哺乳动物中的 LATS1/2）。Hpo 激酶通过与上皮细胞顶域的 Crumbs-Expanded（Crb-Ex）和/或 Merlin-Kibra（Mer-Kib）蛋白结合而被激活。在这里，我们表明 Hpo 的激活还涉及与具有生物分子凝聚物特性的超分子复合物的形成，包括浓度依赖性和对饥饿、大分子拥挤或 1,6-己二醇处理的敏感性。过表达 Ex 或 Kib 会在细胞质中诱导形成微米级的 Hpo 凝聚物，而不是在顶膜上。几个 Hippo 通路成分含有无规卷曲的低复杂度结构域，并且纯化的 Hpo-Sav 复合物在体外发生相分离。Hpo 凝聚物的形成在人细胞中是保守的。我们提出，在上游通路成分聚集诱导的相分离的“信号体”中发生顶端 Hpo 激酶的激活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/64b240f38266/EMBJ-42-e112863-g015.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/09fe1eb34a5d/EMBJ-42-e112863-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/a7892c580851/EMBJ-42-e112863-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/2d88281d72a9/EMBJ-42-e112863-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/f2b19bee4ed4/EMBJ-42-e112863-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/882eeed77ffc/EMBJ-42-e112863-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/b376a420ba76/EMBJ-42-e112863-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/64b240f38266/EMBJ-42-e112863-g015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/689507dff3b9/EMBJ-42-e112863-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/acec4d1a283c/EMBJ-42-e112863-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/51130d12e19e/EMBJ-42-e112863-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/959239a24e3b/EMBJ-42-e112863-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/7c1aba503482/EMBJ-42-e112863-g014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/9659e1c955de/EMBJ-42-e112863-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/6a46555d9ec0/EMBJ-42-e112863-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/09fe1eb34a5d/EMBJ-42-e112863-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/a7892c580851/EMBJ-42-e112863-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/2d88281d72a9/EMBJ-42-e112863-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/f2b19bee4ed4/EMBJ-42-e112863-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/882eeed77ffc/EMBJ-42-e112863-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/b376a420ba76/EMBJ-42-e112863-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/10015380/64b240f38266/EMBJ-42-e112863-g015.jpg

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