PKN3 is the major regulator of angiogenesis and tumor metastasis in mice.
PKN3 is the major regulator of angiogenesis and tumor metastasis in mice.
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DOI：
10.1038/srep18979
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发表时间：
2016-01-08
影响因子：
4.6
通讯作者：
Sugiura R
中科院分区：
文献类型：
--
作者：
Mukai H;Muramatsu A;Mashud R;Kubouchi K;Tsujimoto S;Hongu T;Kanaho Y;Tsubaki M;Nishida S;Shioi G;Danno S;Mehruba M;Satoh R;Sugiura R
PKN是与PKC相关的保守家族成员，是第一个被鉴定为小G蛋白Rho靶点的蛋白激酶。PKN参与多种功能，包括细胞骨架排列和细胞粘附。此外，PKN 3 mRNA在某些癌细胞系中的富集以及其在恶性前列腺细胞生长中的需要表明其参与肿瘤发生。尽管进行了大量的研究，PKN 3在体内的生理和病理作用仍然难以捉摸。在这里，我们产生了PKN 3靶向缺失的小鼠。PKN 3敲除（KO）小鼠存活并正常发育。然而，PKN 3的缺乏对血管生成有影响，如在离体主动脉环测定和体内角膜袋测定中微血管出芽的显著抑制所证明的。此外，当从尾静脉给药时，PKN 3 KO小鼠表现出黑色素瘤细胞的肺转移受损。更重要的是，PKN 3的小干扰RNA（siRNA）敲低诱导细胞表面糖蛋白，包括ICAM-1，整合素β1和整合素α5在HUVECs中的糖基化缺陷。我们的数据提供了第一个体内遗传学证据，PKN 3在血管生成和肿瘤转移中起着关键作用，细胞表面糖蛋白的成熟缺陷可能是这些表型的基础。
PKN, a conserved family member related to PKC, was the first protein kinase identified as a target of the small GTPase Rho. PKN is involved in various functions including cytoskeletal arrangement and cell adhesion. Furthermore, the enrichment of PKN3 mRNA in some cancer cell lines as well as its requirement in malignant prostate cell growth suggested its involvement in oncogenesis. Despite intensive research efforts, physiological as well as pathological roles of PKN3 in vivo remain elusive. Here, we generated mice with a targeted deletion of PKN3. The PKN3 knockout (KO) mice are viable and develop normally. However, the absence of PKN3 had an impact on angiogenesis as evidenced by marked suppressions of micro-vessel sprouting in ex vivo aortic ring assay and in vivo corneal pocket assay. Furthermore, the PKN3 KO mice exhibited an impaired lung metastasis of melanoma cells when administered from the tail vein. Importantly, PKN3 knock-down by small interfering RNA (siRNA) induced a glycosylation defect of cell-surface glycoproteins, including ICAM-1, integrin β1 and integrin α5 in HUVECs. Our data provide the first in vivo genetic demonstration that PKN3 plays critical roles in angiogenesis and tumor metastasis, and that defective maturation of cell surface glycoproteins might underlie these phenotypes.