KITENIN recruits Dishevelled/PKCd to form a functional complex and controls the migration and invasiveness of colorectal cancer cells
KITENIN recruits Dishevelled/PKCd to form a functional complex and controls the migration and invasiveness of colorectal cancer cells
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DOI：
10.1136/gut.2008.150938
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发表时间：
2009-04-01
期刊：
影响因子：
24.5
通讯作者：
Kim, K. K.
中科院分区：
文献类型：
--
作者：
Kho, D. H.;Bae, J. A.;Kim, K. K.
背景和目标：之前报道过，在小鼠结肠肿瘤模型中，KITENIN可促进转移;然而，KITENIN在细胞水平的信号传导机制尚不清楚。在这里，就结直肠癌（CRC）细胞的侵袭和它在CRC tissues.Methods表达的功能作用的KITENIN进行了调查：KITENIN对细胞运动的影响进行了分析，在迁移和侵袭试验后，其过表达和敲低。免疫沉淀被用来阐明结合伙伴，和免疫组化被用来研究expression levels.Results：KITENIN过表达增强大鼠肠上皮细胞的迁移，而在CRC细胞中观察到的侵袭性损失后，KITENIN敲低。从机械上讲，KITENIN作为一种支架分子，通过跨膜C-末端区域同时募集Dishevelled（Dvl）和蛋白激酶C δ（PKC δ），形成一种复合物，通过PKCd组分刺激细胞外信号调节激酶（ERK）/活化蛋白-1（AP-1），但也通过Dvl组分组织肌动蛋白丝。KITENIN复合物控制CRC细胞的侵袭性，所述CRC细胞在病因学上在APC、β-连环蛋白或K-ras中具有各种突变，其中AP-1激活是多余的，但是肌动蛋白丝的组织对于细胞运动是必不可少的。临床上，在结肠癌组织中，从先进的阶段（III，IV）比阶段I CRC和相应的转移tissues.Conclusions：功能性的KITENIN复合物作为一个执行者方面的细胞运动，从而控制CRC细胞的侵袭，这可能有助于促进转移。
Background and aims: KITENIN was previously reported to promote metastasis in mouse colon tumour models; however, the signalling mechanism of KITENIN at the cellular level was unknown. Here the functional role of KITENIN with respect to colorectal cancer (CRC) cell invasion and its expression in CRC tissues were investigated.Methods: The effect of KITENIN on cell motility was analysed in a migration and invasion assay upon its overexpression and knockdown. Immunoprecipitation was used to elucidate binding partners, and immunohistochemistry was used to study expression levels.Results: KITENIN overexpression enhanced the migration of rat intestinal epithelial cells, whereas a loss of invasiveness was observed in CRC cells after KITENIN knockdown. Mechanically, KITENIN served as a scaffolding molecule that simultaneously recruited both Dishevelled (Dvl) and protein kinase C delta (PKC delta) through the membrane-spanning C-terminal region to form a complex that stimulated extracellular signal-regulated kinase (ERK)/activating protein-1 (AP-1) via a PKCd component but also organised the actin filament via a Dvl component. The KITENIN complex controlled the invasiveness of CRC cells aetiologically harbouring various mutations in APC, beta-catenin or K-ras, in which AP-1 activation is redundant but the organisation of the actin filament is indispensable for cell motility. Clinically, KITENIN expression was significantly higher in colon cancer tissues from advanced stage (III, IV) than that of stage I CRC and also in corresponding metastatic tissues.Conclusions: The functional KITENIN complex acts as an executor with regard to cell motility and thereby controls CRC cell invasion, which may contribute to promoting metastasis.