Minor Type IV Collagen α5 Chain Promotes Cancer Progression through Discoidin Domain Receptor-1.
Minor Type IV Collagen α5 Chain Promotes Cancer Progression through Discoidin Domain Receptor-1.
复制标题
次要 IV 型胶原 α 5 链通过 Discoidin 结构域受体 1 促进癌症进展
DOI：
10.1371/journal.pgen.1005249
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发表时间：
2015-05
期刊：
影响因子：
4.5
通讯作者：
Ge G
中科院分区：
文献类型：
--
作者：
Xiao Q;Jiang Y;Liu Q;Yue J;Liu C;Zhao X;Qiao Y;Ji H;Chen J;Ge G
Type IV collagens (Col IV), components of basement membrane, are essential in the maintenance of tissue integrity and proper function. Alteration of Col IV is related to developmental defects and diseases, including cancer. Col IV α chains form α1α1α2, α3α4α5 and α5α5α6 protomers that further form collagen networks. Despite knowledge on the functions of major Col IV (α1α1α2), little is known whether minor Col IV (α3α4α5 and α5α5α6) plays a role in cancer. It also remains to be elucidated whether major and minor Col IV are functionally redundant. We show that minor Col IV α5 chain is indispensable in cancer development by using α5(IV)-deficient mouse model. Ablation of α5(IV) significantly impeded the development of KrasG12D-driven lung cancer without affecting major Col IV expression. Epithelial α5(IV) supports cancer cell proliferation, while endothelial α5(IV) is essential for efficient tumor angiogenesis. α5(IV), but not α1(IV), ablation impaired expression of non-integrin collagen receptor discoidin domain receptor-1 (DDR1) and downstream ERK activation in lung cancer cells and endothelial cells. Knockdown of DDR1 in lung cancer cells and endothelial cells phenocopied the cells deficient of α5(IV). Constitutively active DDR1 or MEK1 rescued the defects of α5(IV)-ablated cells. Thus, minor Col IV α5(IV) chain supports lung cancer progression via DDR1-mediated cancer cell autonomous and non-autonomous mechanisms. Minor Col IV can not be functionally compensated by abundant major Col IV. Collagens, the major extracellular matrix components in most vertebrate tissues, provide cells with structural and functional support. Collagens are trimers of collagen α chains. Multiple trimers are formed by highly homologous α chains for certain types of collagens (e.g. α1α1α2, α3α4α5 and α5α5α6 heterotrimers for type IV collagen). Type IV collagens are named as major type (α1α1α2) or minor type (α3α4α5 and α5α5α6), mainly reflecting the abundance and tissue distribution, but not the importance of their biological functions. High similarity in sequence and domain structure of the α chains does not necessarily imply that major and minor type IV collagens share the same cell surface receptors and intracellular signaling pathways. In this study, we generated an α5(IV) chain deficient mouse model lacking minor type IV collagens. We found that the mutant mice have delayed development of KrasG12D-driven lung cancer without affecting major type IV collagen expression. α5(IV), but not α1(IV), ablation impaired non-integrin collagen receptor discoidin domain receptor-1 (DDR1)-ERK signaling, suggesting that major and minor type IV collagens are functionally distinct from each other.
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影响因子：
8.8
作者：
通讯作者：
--
DOI：
10.1016/j.bbapap.2012.10.014
发表时间：
2013-10
影响因子：
3.2
作者：
Carafoli, Federico;Hohenester, Erhard
通讯作者：
Hohenester, Erhard
DOI：
10.1083/jcb.97.5.1648
发表时间：
1983-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Montesano R;Orci L;Vassalli P
通讯作者：
Vassalli P
影响因子：
4.6
作者：
Pöschl, E;Schlötzer-Schrehardt, U;Mayer, U
通讯作者：
Mayer, U
影响因子：
45.3
作者：
Poon, RTP;Ng, IOL;Wong, J
通讯作者：
Wong, J