EGFR and ADAMs Cooperate to Regulate Shedding and Endocytic Trafficking of the Desmosomal Cadherin Desmoglein 2
EGFR and ADAMs Cooperate to Regulate Shedding and Endocytic Trafficking of the Desmosomal Cadherin Desmoglein 2
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DOI：
10.1091/mbc.e08-04-0356
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发表时间：
2009-01-01
影响因子：
3.3
通讯作者：
Green, Kathleen J.
中科院分区：
文献类型：
--
作者：
Klessner, Jodi L.;Desai, Bhushan V.;Green, Kathleen J.
经典钙粘蛋白的调节在发育和癌症期间的组织重塑中起着关键作用;然而，桥粒钙粘蛋白的重要性受到较少的关注。我们以前表明，EGFR抑制导致桥粒钙粘蛋白，桥粒芯糖蛋白2（Dsg 2），在细胞-细胞界面的抑制基质金属蛋白酶（MMP）依赖性脱落的Dsg 2胞外域和酪氨酸磷酸化的胞质结构域伴随的积累。在这里，我们表明，EGFR抑制稳定Dsg 2在细胞间连接干扰其积累在一个内在的细胞质池。此外，MMP抑制和ADAM 17 RNAi，阻断脱落和耗尽内化Dsg 2，但较少E-钙粘蛋白，在高度侵袭性SCC 68细胞。ADAM 9和15沉默也损害了Dsg 2的加工，支持这种桥粒钙粘蛋白可以由多个ADAM家族成员调节的观点。相反，ADAM 10 siRNA增强了100 kDa Dsg 2切割产物和Dsg 2内化池的积累。虽然MMP和EGFR抑制增加了对照细胞的细胞间粘附强度，但对MMP抑制的反应是Dsg 2依赖性的。这些数据支持的作用，内吞贩运调节桥粒钙粘蛋白的营业额和功能，并提高了内化和调节桥粒和经典钙粘蛋白功能的可能性，可以解耦的机械。
Regulation of classic cadherins plays a critical role in tissue remodeling during development and cancer; however, less attention has been paid to the importance of desmosomal cadherins. We previously showed that EGFR inhibition results in accumulation of the desmosomal cadherin, desmoglein 2 (Dsg2), at cell-cell interfaces accompanied by inhibition of matrix metalloprotease (MMP)-dependent shedding of the Dsg2 ectodomain and tyrosine phosphorylation of its cytoplasmic domain. Here, we show that EGFR inhibition stabilizes Dsg2 at intercellular junctions by interfering with its accumulation in an internalized cytoplasmic pool. Furthermore, MMP inhibition and ADAM17 RNAi, blocked shedding and depleted internalized Dsg2, but less so E-cadherin, in highly invasive SCC68 cells. ADAM9 and 15 silencing also impaired Dsg2 processing, supporting the idea that this desmosomal cadherin can be regulated by multiple ADAM family members. In contrast, ADAM10 siRNA enhanced accumulation of a 100-kDa Dsg2 cleavage product and internalized pool of Dsg2. Although both MMP and EGFR inhibition increased intercellular adhesive strength in control cells, the response to MMP-inhibition was Dsg2-dependent. These data support a role for endocytic trafficking in regulating desmosomal cadherin turnover and function and raise the possibility that internalization and regulation of desmosomal and classic cadherin function can be uncoupled mechanistically.