Glycosylation of FGFR4 in cholangiocarcinoma regulates receptor processing and cancer signaling.
Glycosylation of FGFR4 in cholangiocarcinoma regulates receptor processing and cancer signaling.
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DOI：
10.1002/jcb.30204
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发表时间：
2022-03
影响因子：
4
通讯作者：
Mott JL
中科院分区：
文献类型：
--
作者：
Phillips AJ;Lobl MB;Hafeji YA;Safranek HR;Mohr AM;Mott JL
胆管癌靶向治疗的最新进展集中在成纤维细胞生长因子（FGF）信号转导。有四种受体酪氨酸激酶对FGF有反应，并且已经证明了每种FGF受体的翻译后加工。在这里，我们研究了N-连接的糖基化对FGFR 4的加工和功能的作用。我们通过酶促去糖基化、糖基转移酶的小分子抑制或通过FGFR 4中选定的天冬酰胺残基的定点诱变来改变糖基化。通过半胱天冬酶活化、迁移和FGFR 4的亚细胞定位来测试信号传导。我们的数据表明，FGFR 4具有多种糖型，其中主要条带与具有高甘露糖或混合型形式和复合型聚糖形式的全长受体相关。我们进一步鉴定了一组更快迁移的FGFR 4条带，其对应于称为R4-ICD的细胞内激酶结构域。在人胆管癌肿瘤样品中检测到这些糖型和R4-ICD，其中R4-ICD占主导地位。通过酶促去糖基化去除完整细胞中的聚糖导致R4-ICD的加工增加。使用NGI-1（一种寡糖基转移酶抑制剂）抑制糖基化可降低FGFR 4的高甘露糖或杂合型和复合型聚糖形式，增加加工，并对细胞凋亡敏感。Asn-112、Asn-258、Asn-290或Asn-311突变为谷氨酰胺可适度降低细胞凋亡抗性，而Asn-322突变或其他四个天冬酰胺残基的同时突变可导致FGFR 4细胞保护作用的丧失。没有一种糖突变体改变癌细胞的迁移。最后，Asn-112突变导致FGFR 4部分定位于高尔基体。总的来说，防止单个残基的糖基化降低了FGFR 4的细胞存活功能，并且受体糖基化可以调节FGFR 4对细胞外蛋白酶或蛋白水解敏感性的接近。
Recent advances in targeted treatment for cholangiocarcinoma have focused on fibroblast growth factor (FGF) signaling. There are four receptor tyrosine kinases that respond to FGF’s, and posttranslational processing has been demonstrated for each FGF receptor. Here, we investigated the role of N-linked glycosylation on processing and function of FGFR4. We altered glycosylation through enzymatic deglycosylation, small molecule inhibition of glycosyltransferases, or through site-directed mutagenesis of selected asparagine residues in FGFR4. Signaling was tested through caspase activation, migration, and subcellular localization of FGFR4. Our data demonstrate that FGFR4 has multiple glycoforms, with predominant bands relating to the full-length receptor that has a high mannose- or hybrid-type form and a complex-type glycan form. We further identified a set of faster migrating FGFR4 bands that correspond to the intracellular kinase domain, termed R4-ICD. These glycoforms and R4-ICD were detected in human cholangiocarcinoma tumor samples, where R4-ICD was predominant. Removal of glycans in intact cells by enzymatic deglycosylation resulted in increased processing to R4-ICD. Inhibition of glycosylation using NGI-1, an oligosaccharyltransferase inhibitor, reduced both high mannose- or hybrid- and complex-type glycan forms of FGFR4, increased processing, and sensitized to apoptosis. Mutation of Asn-112, Asn-258, Asn-290, or Asn-311 to glutamine modestly reduced apoptosis resistance, while mutation of Asn-322 or simultaneous mutation of the other four asparagine residues caused a loss of cytoprotection by FGFR4. None of the glycomutants altered migration of cancer cells. Finally, mutation of Asn-112 caused a partial localization of FGFR4 to the Golgi. Overall, preventing glycosylation at individual residues reduced the cell survival function of FGFR4 and receptor glycosylation may regulate access to an extracellular protease or proteolytic susceptibility of FGFR4.
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DOI：
10.1016/j.bbrc.2014.05.115
发表时间：
2014-10-17
影响因子：
3.1
作者：
Takeuchi, Hideyuki;Haltiwanger, Robert S.
通讯作者：
Haltiwanger, Robert S.
影响因子：
--
作者：
Tiong KH;Tan BS;Choo HL;Chung FF;Hii LW;Tan SH;Khor NT;Wong SF;See SJ;Tan YF;Rosli R;Cheong SK;Leong CO
通讯作者：
Leong CO
影响因子：
29.4
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Sia D;Hoshida Y;Villanueva A;Roayaie S;Ferrer J;Tabak B;Peix J;Sole M;Tovar V;Alsinet C;Cornella H;Klotzle B;Fan JB;Cotsoglou C;Thung SN;Fuster J;Waxman S;Garcia-Valdecasas JC;Bruix J;Schwartz ME;Beroukhim R;Mazzaferro V;Llovet JM
通讯作者：
Llovet JM
影响因子：
3.3
作者：
Merilahti, Johannes A. M.;Ojala, Veera K.;Elenius, Klaus
通讯作者：
Elenius, Klaus
DOI：
10.1016/s1357-2725(02)00391-6
发表时间：
2003-05-01
影响因子：
4
作者：
Rodgers, KJ;Dean, RT
通讯作者：
Dean, RT