Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression.
Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression.
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DOI：
10.1016/j.devcel.2011.11.008
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发表时间：
2012-01-17
影响因子：
11.8
通讯作者：
Norman, Jim C.
中科院分区：
文献类型：
--
作者：
Dozynkiewicz, Marta A.;Jamieson, Nigel B.;MacPherson, Iain;Grindlay, Joan;van den Berghe, Peter V. E.;von Thun, Anne;Morton, Jennifer P.;Gourley, Charlie;Timpson, Paul;Nixon, Colin;McKay, Colin J.;Carter, Ross;Strachan, David;Anderson, Kurt;Sansom, Owen J.;Caswell, Patrick T.;Norman, Jim C.
在这里，我们表明Rab 25允许将配体占据的活性构象α5β1整合素分选到晚期内体/溶酶体。光活化和生物化学方法表明，溶酶体靶向的整合素不降解，但逆行运输和再循环到侵入细胞后面的质膜。这需要CLIC 3，一种在Rab 25表达细胞和肿瘤中上调的蛋白质，其与晚期内体/溶酶体中的活性α5β1共定位。CLIC 3是在3D基质上迁移期间释放细胞后部所必需的，并且是在器官型微环境中侵袭和维持活性Src信号传导所必需的。CLIC 3表达预测胰腺导管腺癌（PDAC）可手术病例的淋巴结转移和不良预后。CLIC 3作为再循环途径的调节剂和PDAC中的独立预后指标的鉴定突出了活性整联蛋白运输作为体内癌症进展的潜在驱动力的重要性。活化的整合素从晚期内体/溶酶体移动到质膜。活化和非活化整合素再循环途径的空间分离。Rab CLIC 3调节细胞迁移和侵袭。Rab CLIC 3决定Rab 25是否作为癌症进展抑制剂或促进剂发挥作用。
Here we show that Rab25 permits the sorting of ligand-occupied, active-conformation α5β1 integrin to late endosomes/lysosomes. Photoactivation and biochemical approaches show that lysosomally targeted integrins are not degraded but are retrogradely transported and recycled to the plasma membrane at the back of invading cells. This requires CLIC3, a protein upregulated in Rab25-expressing cells and tumors, which colocalizes with active α5β1 in late endosomes/lysosomes. CLIC3 is necessary for release of the cell rear during migration on 3D matrices and is required for invasion and maintenance of active Src signaling in organotypic microenvironments. CLIC3 expression predicts lymph node metastasis and poor prognosis in operable cases of pancreatic ductal adenocarcinoma (PDAC). The identification of CLIC3 as a regulator of a recycling pathway and as an independent prognostic indicator in PDAC highlights the importance of active integrin trafficking as a potential drive to cancer progression in vivo. ► Activated integrins move from late endosomes/lysosomes to the plasma membrane ► Spatial segregation of pathways recycling active and inactive integrins ► CLIC3 regulates cell migration and invasion ► CLIC3 dictates whether Rab25 functions as cancer progression suppressor or promoter
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影响因子：
3.3
作者：
Lee, JW;Juliano, RL
通讯作者：
Juliano, RL
DOI：
10.1083/jcb.153.7.1427
发表时间：
2001-06-25
期刊：
The Journal of cell biology
影响因子：
--
作者：
Laukaitis CM;Webb DJ;Donais K;Horwitz AF
通讯作者：
Horwitz AF
影响因子：
56.9
作者：
Cukierman, E;Pankov, R;Yamada, KM
通讯作者：
Yamada, KM
影响因子：
11.8
作者：
Lobert, Viola Helene;Brech, Andreas;Stenmark, Harald
通讯作者：
Stenmark, Harald
影响因子：
15.9
作者：
Nam, Ki Taek;Lee, Hyuk-Joon;Goldenring, James R.
通讯作者：
Goldenring, James R.