Smoothened (SMO) regulates insulin-like growth factor 1 receptor (IGF1R) levels and protein kinase B (AKT) localization and signaling.
Smoothened (SMO) regulates insulin-like growth factor 1 receptor (IGF1R) levels and protein kinase B (AKT) localization and signaling.
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DOI：
10.1038/s41374-021-00702-6
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Landgraf R
中科院分区：
文献类型：
--
作者：
Agarwal NK;Kim CH;Kunkalla K;Vaghefi A;Sanchez S;Manuel S;Bilbao D;Vega F;Landgraf R
Smoothened（SMO）癌蛋白是一种卷曲G蛋白偶联受体，是Hedgehog（Hh）信号转导的中心。虽然在纤毛的背景下最好地理解规范SMO信号传导，但证据表明SMO在癌症生物学中具有与规范Hh信号传导无关的其他功能。在此，我们提供的证据表明，人类SMO水平升高与IGF 1 R水平升高和DLBCL生存率降低密切相关。作为筏微结构域的一个组成部分，SMO在维持淋巴瘤和乳腺癌细胞中IGF 1 R水平以及IGF 1 R相关的AKT激活中起着重要作用。SMO的沉默增加了溶酶体降解，并有利于IGF 1 R定位于晚期内体区室，而不是早期内体区室，其中大部分受体通常会再循环。此外，SMO的缺失干扰了脂筏定位和剩余IGF 1 R和AKT的保留，从而破坏了IGF 1 R/AKT的主要信号传导背景。SMO的这种活性不依赖于其经典信号传导，并且代表了高度致癌的IGF 1 R/AKT信号传导轴对信号传导的新的和临床相关的贡献。
The oncoprotein Smoothened (SMO), a Frizzled-class-G-protein-coupled receptor, is the central transducer of Hedgehog (Hh) signaling. While canonical SMO signaling is best understood in the context of cilia, evidence suggests that SMO has other functions in cancer biology that are unrelated to canonical Hh signaling. Herein, we provided evidence that elevated levels of human SMO show a strong correlation with elevated levels of IGF1R and reduced survival in DLBCL. As an integral component of raft microdomains, SMO plays a fundamental role in maintaining the levels of IGF1R in lymphoma and breast cancer cells as well IGF1R associated activation of AKT. Silencing of SMO increases lysosomal degradation and favors a localization of IGF1R to late endosomal compartments instead of early endosomal compartments from which much of the receptor would normally recycle. In addition, loss of SMO interferes with the lipid raft localization and retention of the remaining IGF1R and AKT, thereby disrupting the primary signaling context for IGF1R/AKT. This activity of SMO is independent of its canonical signaling and represents a novel and clinically relevant contribution to signaling by the highly oncogenic IGF1R/AKT signaling axis.
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影响因子：
50.3
作者：
Chen L;Monti S;Juszczynski P;Ouyang J;Chapuy B;Neuberg D;Doench JG;Bogusz AM;Habermann TM;Dogan A;Witzig TE;Kutok JL;Rodig SJ;Golub T;Shipp MA
通讯作者：
Shipp MA
影响因子：
4.8
作者：
Agarwal, Nitin K.;Qu, Changju;Vega, Francisco
通讯作者：
Vega, Francisco
影响因子：
5.6
作者：
Madhala-Levy, D.;Williams, V. C.;Hughes, S. M.;Reshef, R.;Halevy, O.
通讯作者：
Halevy, O.
DOI：
10.1073/pnas.1305656110
发表时间：
2013-07-23
影响因子：
11.1
作者：
Pfeifer, Matthias;Grau, Michael;Lenz, Georg
通讯作者：
Lenz, Georg
影响因子：
6.5
作者：
Calay, Damien;Vind-Kezunovic, Dina;Gniadecki, Robert
通讯作者：
Gniadecki, Robert