Activated leukocyte cell adhesion molecule (ALCAM/CD166/MEMD), a novel actor in invasive growth, controls matrix metalloproteinase activity
Activated leukocyte cell adhesion molecule (ALCAM/CD166/MEMD), a novel actor in invasive growth, controls matrix metalloproteinase activity
复制标题
DOI：
10.1158/0008-5472.can-05-0378
复制
发表时间：
2005-10-01
期刊：
影响因子：
11.2
通讯作者：
Swart, GWM
中科院分区：
文献类型：
--
作者：
Lunter, PC;van Kilsdonk, JWJ;Swart, GWM
活化白细胞细胞黏附分子（ALCAM/CD166/MEMD）可作为细胞密度的细胞表面传感器，在黑色素瘤进展过程中控制局部细胞增殖和组织侵袭之间的转变。我们已经验证了这样一个假设：渐进性的细胞聚集控制着明胶酶A/基质金属蛋白酶 - 2（MMP - 2）激活的蛋白水解级联反应，这涉及到膜型1基质金属蛋白酶（MT1 - MMP/MMP - 14）、金属蛋白酶组织抑制剂 - 2（TIMP - 2）和前体MMP - 2在细胞表面形成一个中间三元复合物。令人惊讶的是，在裸鼠异种移植模型中，ALCAM的截断严重损害了MMP - 2的激活，我们之前在该模型中观察到原发性肿瘤生长减少和黑色素瘤转移增强。对二维单层培养和三维胶原凝胶培养的比较研究表明，广泛的细胞间接触、野生型ALCAM以及细胞与基质的相互作用对于转移性黑色素瘤细胞中前体MMP - 2高效转化为其活性形式都是必不可少的。截短的显性负性ALCAM通过降低转录水平和减少MT1 - MMP的加工来减弱MMP - 2的激活。通过RNA干扰选择性去除ALCAM后蛋白水解级联反应失败主要是由于MT1 - MMP加工不完全，而广泛的细胞间接触原本可促进这种加工。这些数据赋予ALCAM在蛋白水解调节中的一种新的信号传导作用，并支持其先前假定的在侵袭性生长中的传感器功能。
Activated leukocyte cell adhesion molecule (ALCAM/CD166/ MEMD) could function as a cell surface sensor for cell density, controlling the transition between local cell proliferation and tissue invasion in melanoma progression. We have tested the hypothesis that progressive cell clustering controls the proteolytic cascade for activation of gelatinase A/matrix metalloproteinase-2 (NIMP-2), which involves formation of an intermediate ternary complex of membrane type 1 MMP (MT1-MMP/MMP-14), tissue inhibitor of metalloproteinase-2 (TIMP-2), and pro-MMP-2 at the cell surface. Surprisingly, truncation of ALCAM severely impaired NIMP-2 activation in a nude mouse xenograft model, in which we previously observed diminished primary tumor growth and enhanced melanoma metastasis. Comparative studies of two-dimensional monolayer and three-dimensional,collagen-gel cultures revealed that extensive cell-to-cell contacts, wildtype ALCAM, and cell-to-matrix interactions were all indispensable for efficient conversion of pro-MMP-2 to its active form in metastatic melanoma cells. Truncated, dominant-negative ALCAM diminished MMP-2 activation via reduced transcript levels and decreased processing of MT1-MMP. Failure of the proteolytic cascade after selective ALCAM depletion by RNA interference was mainly due to incomplete MT1-MMP processing, which was otherwise promoted by extensive cell-to-cell contacts. These data attribute a novel signaling role to ALCAM in regulation of proteolysis and support its previously postulated sensor function in invasive growth.