An RGD Motif Present in Cadherin 17 Induces Integrin Activation and Tumor Growth
An RGD Motif Present in Cadherin 17 Induces Integrin Activation and Tumor Growth
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DOI：
10.1074/jbc.m114.600502
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发表时间：
2014-12-12
影响因子：
4.8
通讯作者：
Ignacio Casal, J.
中科院分区：
文献类型：
--
作者：
Bartolome, Ruben A.;Pelaez-Garcia, Alberto;Ignacio Casal, J.
背景：钙粘蛋白17和21整合素相互作用促进细胞黏附和增殖。结果：钙粘蛋白17含有一个RGD基序，构成整合素结合和激活的关键开关。结论：钙粘蛋白RGD基序是肿瘤生长和转移的关键配体。意义：钙粘蛋白17是第一个已知的整合素配体RGD-钙粘蛋白。其他RGD-钙粘附素可能在肿瘤转移中发挥重要作用。对钙粘附素17(CDH17)激活整合素的机制知之甚少。在这里，我们观察到在人CDH17序列的第6区存在一个三肽基序RGD，以及其他钙粘附素，如钙粘蛋白5和钙粘附素6。CDH17 RAD突变体的使用表明，RKO和KM12SM结肠癌细胞的增殖和黏附显著降低。此外，RGD多肽抑制了两种细胞对重组CDH17结构域6的黏附。外源RGD基序可引起1整合素转变为高亲和力的活性构象，并增加粘着斑激酶和ERK1/2的激活。用瑞士裸鼠进行的体内实验表明，表达CDH17 RAD突变体的癌细胞在肿瘤生长和肝脏归巢方面表现出相当大的延迟。CDH17的RGD效应在胰腺癌细胞中也很活跃。我们的结果表明，21整合素通过两个不同的结合部位与IV型胶原和CDH17这两种不同的配体相互作用。总之，RGD结合基序构成了整合素途径激活的开关，并显示了CDH17作为整合素配体的新能力。这个基序可以作为靶点，以避免在过度表达CDH17和其他含RGD的钙粘附素的肿瘤中转移扩散。
Background: The interaction between cadherin 17 and 21 integrin promotes cell adhesion and proliferation. Results: Cadherin 17 contains an RGD motif that constitutes the critical switch for integrin binding and activation. Conclusion: The cadherin RGD motif is a critical ligand for tumor growth and metastasis. Significance: Cadherin 17 is the first known integrin-ligand RGD-cadherin. Other RGD-cadherins might play important roles in cancer metastasis.Little is known about the mechanism of integrin activation by cadherin 17 (CDH17). Here we observed the presence of a tri-peptide motif, RGD, in domain 6 of the human CDH17 sequence and other cadherins such as cadherin 5 and cadherin 6. The use of CDH17 RAD mutants demonstrated a considerable decrease of proliferation and adhesion in RKO and KM12SM colon cancer cells. Furthermore, RGD peptides inhibited the adhesion of both cell lines to recombinant CDH17 domain 6. The RGD motif added exogenously to the cells provoked a change in 1 integrin to an active, high-affinity conformation and an increase in focal adhesion kinase and ERK1/2 activation. In vivo experiments with Swiss nude mice demonstrated that cancer cells expressing the CDH17 RAD mutant showed a considerable delay in tumor growth and liver homing. CDH17 RGD effects were also active in pancreatic cancer cells. Our results suggest that 21 integrin interacts with two different ligands, collagen IV and CDH17, using two different binding sites. In summary, the RGD binding motif constitutes a switch for integrin pathway activation and shows a novel capacity of CDH17 as an integrin ligand. This motif could be targeted to avoid metastatic dissemination in tumors overexpressing CDH17 and other RGD-containing cadherins.