A CONFINED VARIABLE REGION CONFERS LIGAND SPECIFICITY ON FIBROBLAST GROWTH-FACTOR RECEPTORS - IMPLICATIONS FOR THE ORIGIN OF THE IMMUNOGLOBULIN FOLD
A CONFINED VARIABLE REGION CONFERS LIGAND SPECIFICITY ON FIBROBLAST GROWTH-FACTOR RECEPTORS - IMPLICATIONS FOR THE ORIGIN OF THE IMMUNOGLOBULIN FOLD
复制标题
DOI：
10.1002/j.1460-2075.1992.tb05240.x
复制
发表时间：
1992-05-01
期刊：
影响因子：
11.4
通讯作者：
GIVOL, D
中科院分区：
文献类型：
--
作者：
YAYON, A;ZIMMER, Y;GIVOL, D
细胞生长因子与其受体的结合构成了高度特异性的相互作用，是细胞和组织类型特异性生长和分化的基础。成纤维细胞生长因子受体的一个独特特征是具有多种结构变体以及受体与其不同配体之间前所未有的交叉反应程度。为了检测这些生长因子和受体家族中的受体-配体特异性，我们使用基因工程来替换Bek/FGFR2和密切相关的角质形成细胞生长因子受体(KGFR)之间的离散区域。我们证明了BEK和KGFR的第三个免疫球蛋白样区中的一个受限的、50个氨基酸的可变区唯一地决定了它们的配体结合特异性。用相应的KGFR序列替换BEK/FGFR2的可变区，导致了一个与KGF结合的嵌合受体，而失去了与碱性成纤维细胞生长因子结合的能力。我们提供的证据表明，这两个可变序列是由两个不同的外显子编码的，这两个外显子在小鼠基因组中映射得很近，并遵循一个恒定的外显子，这表明这两个受体是由一个共同的基因通过互斥的选择性mRNA剪接而来的。这些结果证实了成纤维细胞生长因子受体第三个免疫球蛋白样结构域的C末端一半是配体结合的主要决定因素，并为改变受体-配体特异性和产生受体多样性提供了一种新的遗传机制。
Binding of cellular growth factors to their receptors constitutes a highly specific interaction and the basis for cell and tissue-type specific growth and differentiation. A unique feature of fibroblast growth factor (FGF) receptors is the multitude of structural variants and an unprecedented degree of cross-reactivity between receptors and their various ligands. To examine receptor-ligand specificity within these families of growth factors and receptors, we used genetic engineering to substitute discrete regions between Bek/FGFR2 and the closely related keratinocyte growth factor receptor (KGFR). We demonstrate that a confined, 50 amino acid, variable region within the third immunoglobulin-like domain of Bek and KGFR exclusively determines their ligand binding specificities. Replacing the variable region of Bek/FGFR2 with the corresponding sequence of KGFR resulted in a chimeric receptor which bound KGF and had lost the capacity to bind basic FGF. We present evidence that the two variable sequences are encoded by two distinct exons that map close together in the mouse genome and follow a constant exon, suggesting that the two receptors were derived from a common gene by mutually exclusive alternative mRNA splicing. These results identify the C-terminal -half of the third immunoglobulin-like domain of FGF receptors as a major determinant for ligand binding and present a novel genetic mechanism for altering receptor-ligand specificity and generating receptor diversity.