MOLECULAR-CLONING OF FIBROBLAST ACTIVATION PROTEIN-ALPHA, A MEMBER OF THE SERINE-PROTEASE FAMILY SELECTIVELY EXPRESSED IN STROMAL FIBROBLASTS OF EPITHELIAL CANCERS
MOLECULAR-CLONING OF FIBROBLAST ACTIVATION PROTEIN-ALPHA, A MEMBER OF THE SERINE-PROTEASE FAMILY SELECTIVELY EXPRESSED IN STROMAL FIBROBLASTS OF EPITHELIAL CANCERS
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DOI：
10.1073/pnas.91.12.5657
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发表时间：
1994-06-07
影响因子：
11.1
通讯作者：
RETTIG, WJ
中科院分区：
文献类型：
--
作者：
SCANLAN, MJ;RAJ, BKM;RETTIG, WJ
人成纤维细胞活化蛋白α（FAPα）是一种分子量为95000的细胞表面抗原，选择性地表达于上皮癌的反应性基质成纤维细胞、愈合伤口的肉芽组织以及骨和软组织肉瘤的恶性细胞中。正常成人组织通常不表达FAPα，但一些胎儿间充质组织会短暂表达该分子。由于其在正常组织中的分布有限，且在超过90%的乳腺癌、结直肠癌和肺癌的基质中大量表达，FAPα正在作为上皮癌免疫检测和免疫治疗的靶点进行临床评估。在本研究中，我们通过在COS - 1细胞中进行表达克隆，分离出了FAPα的全长cDNA。FAPα cDNA编码一种II型整合膜蛋白，具有一个大的细胞外结构域、跨膜区段和短的细胞质尾。FAPα与T细胞活化抗原CD26有48%的氨基酸序列同一性，CD26是一种具有二肽基肽酶IV（DPPIV）活性的膜结合蛋白；然而，与FAPα不同的是，CD26在正常组织中广泛表达。不同物种的DPPIV同源物以及其他丝氨酸蛋白酶共有的三个催化结构域在FAPα中是保守的。对共表达FAPα和CD26的COS - 1细胞进行的免疫化学分析表明，这两种分子形成异源二聚体细胞表面复合物；这表明先前在培养的成纤维细胞和生长因子刺激的黑素细胞中鉴定的与FAPα相关的分子量为105000的蛋白质FAPβ与CD26是相同的。在体内，FAPα和CD26在愈合伤口的反应性成纤维细胞中共表达，但在肿瘤基质成纤维细胞或肉瘤中不共表达（FAPα阳性/CD26阴性）。FAPα假定的丝氨酸蛋白酶活性及其在体内的诱导模式可能表明该分子在发育、组织修复和上皮癌变过程中对成纤维细胞生长或上皮 - 间充质相互作用的控制中起作用。
The human fibroblast activation protein alpha (FAP alpha) is a M(r) 95,000 cell surface antigen selectively expressed in reactive stromal fibroblasts of epithelial cancers, granulation tissue of healing wounds, and malignant cells of bone and soft tissue sarcomas. Normal adult tissues are generally FAP alpha(-), but some fetal mesenchymal tissues transiently express the molecule. Because of its restricted normal tissue distribution and abundant expression in the stroma of over 90% of breast, colorectal, and lung carcinomas, FAP alpha is under clinical evaluation as a target for immunodetection and immunotherapy of epithelial cancers. In the present study, we have isolated a full-length cDNA for FAP alpha through expression cloning in COS-1 cells. The FAP alpha cDNA codes for a type II integral membrane protein with a large extracellular domain, transmembrane segment, and short cytoplasmic tail. FAP alpha shows 48% amino acid sequence identity to the T-cell activation antigen CD26, a membrane-bound protein with dipeptidyl peptidase ni (DPPIV) activity; however, unlike FAP alpha, CD26 is widely expressed in normal tissues. Three catalytic domains shared by DPPIV homologues in different species and by other serine proteases are conserved in FAP alpha. Immunochemical analysis of COS-1 cells coexpressing FAP alpha and CD26 revealed that the two molecules form heteromeric cell surface complexes; suggesting that a previously identified FAP alpha-associated M(r) 105,000 protein of cultured fibroblasts and growth factor-stimulated melanocytes, FAP beta, is identical to CD26. In vivo coexpression of FAP alpha and CD26 is found in reactive fibroblasts of healing wounds but not in tumor stromal fibroblasts or sarcomas (FAP alpha(+)/CD26(-)). The putative serine protease activity of FAP alpha and its in vivo induction pattern may indicate a role for this molecule in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis.