Plasma-membrane-associated sialidase (NEU3) differentially regulates integrin-mediated cell proliferation through laminin- and fibronectin-derived signalling
Plasma-membrane-associated sialidase (NEU3) differentially regulates integrin-mediated cell proliferation through laminin- and fibronectin-derived signalling
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DOI：
10.1042/bj20050737
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发表时间：
2006-03-15
影响因子：
4.1
通讯作者：
Miyagi, T
中科院分区：
文献类型：
--
作者：
Kato, K;Shiga, K;Miyagi, T
我们以前已经发现，人质膜相关唾液酸酶（NEU 3），神经节苷脂降解的关键糖苷酶。在人结肠癌中显著上调，参与细胞凋亡的抑制。为了阐明NEU 3表达增加的分子机制，在本研究中，我们研究了其在人结肠癌细胞粘附中的作用。与对照细胞相比，NEU 3转染的DLD-1细胞表现出对层粘连蛋白的粘附增加和随之而来的细胞增殖，但对纤连蛋白和胶原蛋白I和IV的细胞粘附减少。当被层粘连蛋白触发时，NEU 3明显刺激FAK（粘着斑激酶）和ERK（细胞外信号调节激酶）的磷酸化，而纤连蛋白上没有激活。仅在层粘连蛋白-5上，NEU 3通过募集Shc和Grb-2显著增强整联蛋白β 4的酪氨酸磷酸化，并且NEU 3被抗（整联蛋白β 4）抗体共免疫沉淀，表明NEU 3与整联蛋白β 4的缔合可能促进层粘连蛋白-5上整联蛋白衍生的信号传导。此外，还在层粘连蛋白上观察到整合素β 1和ILK（整合素连接激酶）磷酸化的促进作用。通过TLC评估，作为NEU 3过表达的结果的G（M3）消耗似乎是层粘连蛋白上的粘附增加的原因之一，相反，是纤连蛋白上的粘附减少的原因之一-NEU 3可能具有双峰效应。这些结果表明，NEU 3通过依赖于细胞外基质的整合素介导的信号传导差异调节细胞增殖，并且在层粘连蛋白上，NEU 3确实激活了在癌发生中经常上调的分子，这可能导致癌细胞中恶性表型的加速。
We have found previously that human plasma-membrane-associated sialidase (NEU3), a key glycosidase for ganglioside degradation. was markedly up-regulated in human colon cancers, with an involvement in suppression of apoptosis. To elucidate the molecular mechanisms underlying increased NEU3 expression, in the present study we investigated its role in cell adhesion of human colon cancer cells. DLD-1 cells transfected with NEU3 exhibited increased adhesion to laminins and consequent cell proliferation, but decreased cell adhesion to fibronectin and collagens I and IV, compared with control cells. When triggered by laminins, NEU3 clearly stimulated phosphorylation of FAK (focal adhesion kinase) and ERK (extracellular-signal-regulated kinase), whereas there was no activation on fibronectin. NEU3 markedly enhanced tyrosine phosphorylation of integrin beta 4 with recruitment of Shc and Grb-2 only on laminin-5, and NEU3 was co-immunoprecipitated by an anti-(integrin beta 4) antibody, suggesting that association of NEU3 with integrin beta 4 might facilitate promotion of the integrin-derived signalling on laminin-5. In addition, the promotion of phosphorylation of integrin beta 1 and ILK (integrin-linked kinase) was also observed on laminins. G(M3) depletion as the result of NEU3 overexpression, assessed by TLC, appeared to be one of the causes of the increased adhesion on laminins and, in contrast, of the decreased adhesion on fibronectin - NEU3 probably having bimodal effects. These results indicate that NEU3 differentially regulates cell proliferation through integrin-mediated signalling depending on the extracellular matrix and, on laminins, NEU3 did indeed activate molecules often up-regulated in carcinogenesis, which may cause an acceleration of the malignant phenotype in cancer cells.