子宮內膜異位症是指子宮內膜組織生長在子宮腔以外的任何部位，屬於婦科中最常見的慢性疾病。不幸的是臨床上並沒有有效治療子宮內膜異位症的方法，因此研究子宮內膜異位症病理機制是必要的。以過往我們實驗室研究發現一個具有細胞外基質的貼附功能的膜蛋白，炭疽毒素受體-2，其表現量在子宮內膜的異位組織中有上升的趨勢。不正常大量表現的炭疽毒素受體-2甚至可以藉由增加YAP1細胞核轉移與下游基因的轉錄活性，促進子宮內膜細胞的沾黏能力和存活能力。然而，炭疽毒素受體-2如何調控YAP1細胞核轉移的機制尚未清楚。先前實驗室藉由生物資訊的方式，推測hippo信號路徑可能是炭疽毒素受體-2的潛在調控下游分子路徑。因此我們假設炭疽毒素受體-2也許與hippo信號路徑當中的分子相互作用，影響YAP1細胞核轉移。接下來，我們利用炭疽毒素受體-2的抗體，在子宮內膜異位症患者的異位基質細胞做免疫沉澱，發現hippo信號路徑MST激酶的骨架蛋白SAV1可以與炭疽毒素受體-2一起被沉澱下來。為了瞭解是否炭疽毒素受體-2藉由結合SAV1來參與在子宮內膜異位症的進程，我們轉染質體到人類胚胎腎細胞，來過度表達野生型或突變的炭疽毒素受體-2和SAV1，在免疫沉澱法下觀察這兩個蛋白會透過何種特定的結構域。起初我們發現即使剔除炭疽毒素受體-2蛋白質序列C端121個胺基酸後，SAV1仍然可以與突變的炭疽毒素受體-2一起被沉澱下來。分析突變炭疽毒素受體-2在細胞內剩餘的胺基酸後，我們預測炭疽毒素受體-2序列上有一個富脯氨酸模體，有很高的機率與SAV1上的雙色胺酸結構域結合。結果顯示，當SAV1上的雙色胺酸結構域被突變或炭疽毒素受體-2上的富脯氨酸模體被剔除後，便消除兩個蛋白的交互作用。總結來說，我們的結果進一步說明炭疽毒素受體-2可以透過結合SAV1，影響YAP1細胞核轉移和下游基因轉錄活性，促使子宮內膜異位症進程。

Endometriosis, characterized by the presence of endometrial tissue outside the uterine cavity, is one of the most common chronic gynecological diseases. Unfortunately, there is no cure for this disease. Therefore, it is important to elucidate the underlying mechanism of endometriosis development. Our laboratory has previously shown that anthrax toxin receptor 2 (ANTXR2) is aberrantly expressed in endometriotic cells and overexpression of ANTXR2 promotes endometriotic cells adhesion and survival through an increase of Yes-associated protein 1 (YAP1) nuclear translocation and transcriptional activity. However, how ANTXR2 regulates YAP1 activation remains uncharacterized. Since Hippo pathway is one of potential ANTXR2-regulated signaling pathways under bioinformatic analysis, we hypothesized that ANTXR2 signaling may cross-talk with Hippo pathway through protein-protein interaction upstream of YAP1. Herein, we found Salvador homolog 1 (SAV1), the scaffold protein of MST kinase (Hippo orthologue), can be pulled down by anti-ANTXR2 antibody in endometriotic stromal cell via immunoprecipitation assay. To test whether ANTXR2-SAV1 interaction involves in endometriosis development, the human embryonic kidney cells (HEK293FT) were used to investigate how ANTXR2 binds to SAV1. Overexpression of wildtype or mutant ANTXR2 and SAV1 were achieved through plasmid transfection. We found that SAV1 could interact with ANTXR2 even though the C-terminal 121 amino acids were deleted. After analyzing the remaining intracellular domain of ANTXR2, a proline-rich motif was predicted to have high possibility to bind SAV1 at the WW domain. In our results, when the WW domain of SAV1 was mutated or the proline-rich motif of ANTXR2 was deleted, the interaction between ANTXR2 and SAV1 was abolished. Collectively, our results so far suggested that ANTXR2 affects YAP1 nuclear translocation and activity in endometriotic cells is via cross-talking with Hippo pathway by binding to the SAV1.

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