The Tumor Suppressor Activity of the Transmembrane Protein with Epidermal Growth Factor and Two Follistatin Motifs 2 (TMEFF2) Correlates with Its Ability to Modulate Sarcosine Levels
The Tumor Suppressor Activity of the Transmembrane Protein with Epidermal Growth Factor and Two Follistatin Motifs 2 (TMEFF2) Correlates with Its Ability to Modulate Sarcosine Levels
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DOI：
10.1074/jbc.m110.193805
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发表时间：
2011-05-06
影响因子：
4.8
通讯作者：
Ruiz-Echevarra, Maria J.
中科院分区：
文献类型：
--
作者：
Chen, Xiaofei;Overcash, Ryan;Ruiz-Echevarra, Maria J.
具有表皮生长因子和两个卵泡抑素基序 2 的 I 型跨膜蛋白 (TMEFF2) 在大脑和前列腺中表达，并在前列腺癌中过度表达，但其在这种疾病中的作用尚不清楚。一些研究表明，TMEFF2 在抑制人类癌细胞的生长和侵袭潜力方面发挥作用，而其他研究则表明，TMEFF2 缺乏细胞质区域的脱落部分具有促进生长的活性。在这里，我们展示了 TMEFF2 具有双重作用模式。野生型全长 TMEFF2 的异位表达可抑制软琼脂集落形成、细胞侵袭和迁移，并增加细胞对细胞凋亡的敏感性。然而，TMEFF2 胞外域部分的表达会增加细胞增殖。使用亲和色谱和质谱分析，我们将肌氨酸脱氢酶 (SARDH)（一种将肌氨酸转化为甘氨酸的酶）鉴定为 TMEFF2 相互作用蛋白。免疫共沉淀和免疫荧光分析证实了 SARDH 与全长 TMEFF2 的相互作用。胞外域不与 SARDH 结合。此外，全长 TMEFF2 的表达而非胞外域的表达导致细胞中肌氨酸水平降低。这些结果表明，TMEFF2 的肿瘤抑制活性需要该蛋白的细胞质/跨膜部分，并与其结合 SARDH 和调节肌氨酸水平的能力相关。
The type I transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is expressed in brain and prostate and overexpressed in prostate cancer, but its role in this disease is unclear. Several studies have suggested that TMEFF2 plays a role in suppressing the growth and invasive potential of human cancer cells, whereas others suggest that the shed portion of TMEFF2, which lacks the cytoplasmic region, has a growth-promoting activity. Here we show that TMEFF2 has a dual mode of action. Ectopic expression of wild-type full-length TMEFF2 inhibits soft agar colony formation, cellular invasion, and migration and increases cellular sensitivity to apoptosis. However, expression of the ectodomain portion of TMEFF2 increases cell proliferation. Using affinity chromatography and mass spectrometry, we identify sarcosine dehydrogenase (SARDH), the enzyme that converts sarcosine to glycine, as a TMEFF2-interacting protein. Co-immunoprecipitation and immunofluorescence analysis confirms the interaction of SARDH with full-length TMEFF2. The ectodomain does not bind to SARDH. Moreover, expression of the full-length TMEFF2 but not the ectodomain results in a decreased level of sarcosine in the cells. These results suggest that the tumor suppressor activity of TMEFF2 requires the cytoplasmic/transmembrane portion of the protein and correlates with its ability to bind to SARDH and to modulate the level of sarcosine.