Department of Oncology, Cambridge University, Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, U.K.
Cell Biol Int. 2011 Oct;35(10):1043-53. doi: 10.1042/CBI20100885.
ADAMs (a disintegrin and metalloproteinase) are a family of type I transmembrane glycoproteins related to snake venom metalloproteases and disintegrins. They are regulatory proteins that modulate intercellular adhesion and the bioavailability of growth factors, and have been implicated in many disease states, including cancer, immunity and inflammation. One member of the ADAM family, ADAM28, has been reported to bind to the integrin α4β1 in humans; however, the distribution of ADAM28 and the biological consequences of ADAM28-α4β1 interactions are yet to be fully elucidated. The expression of ADAM28 in human and murine tissues was examined by multiple Affymetrix microarray analyses, real-time RT-PCR (reverse transcription-PCR) and immunohistochemical staining. We found that ADAM28 has a relatively restricted expression pattern in mouse and human and is highly expressed in the B-lymphocyte lineage, including chronic lymphocytic leukaemic B-cells. The murine B-lymphoma line L1-2 and recombinant soluble murine ADAM28 were used to investigate ADAM28-α4β1 interactions. Our data reveal that ADAM28 binding to α4β1 is typical of integrin-ligand interactions, since it is attenuated by anti-functional integrin antibodies, and is enhanced by Mn2+ and the integrin mAb (monoclonal antibody) 9EG7. However, a key finding was that soluble ADAM28 unexpectedly enhanced α4β1-dependent cell adhesion to VCAM-1 (vascular cell adhesion molecule-1). In so doing ADAM28 was able to influence lymphocyte adhesion to, and migration through, endothelial monolayers, suggesting a physiological role for ADAM28 in regulating the specific spatial and temporal transendothelial migration of lymphocytes.
解整合素金属蛋白酶（ADAMs）是一类与蛇毒金属蛋白酶和解整合素相关的Ⅰ型跨膜糖蛋白家族。它们是调节细胞间黏附及生长因子生物利用度的调节蛋白，与许多疾病状态有关，包括癌症、免疫和炎症。ADAM 家族的一个成员 ADAM28 已被报道与人整合素 α4β1 结合；然而，ADAM28 的分布以及 ADAM28-α4β1 相互作用的生物学后果尚未完全阐明。通过多重 Affymetrix 微阵列分析、实时 RT-PCR（逆转录-PCR）和免疫组织化学染色来检查 ADAM28 在人和鼠组织中的表达。我们发现 ADAM28 在人和鼠中的表达模式相对受限，在 B 淋巴细胞谱系中高度表达，包括慢性淋巴细胞白血病 B 细胞。使用鼠 B 淋巴瘤系 L1-2 和重组可溶性鼠 ADAM28 来研究 ADAM28-α4β1 相互作用。我们的数据表明，ADAM28 与 α4β1 的结合是典型的整合素-配体相互作用，因为它被抗功能性整合素抗体减弱，并被 Mn2+和整合素 mAb（单克隆抗体）9EG7 增强。然而，一个关键的发现是，可溶性 ADAM28 出人意料地增强了 α4β1 依赖性细胞黏附到 VCAM-1（血管细胞黏附分子-1）。这样，ADAM28 能够影响淋巴细胞黏附到并穿过内皮单层，表明 ADAM28 在调节淋巴细胞特定的时空穿越内皮迁移中具有生理作用。
