Alexander J M, Bikkal H A, Zervas N T, Laws E R, Klibanski A
Department of Medicine, Massachusetts General Hospital, Boston 02114, USA.
J Clin Endocrinol Metab. 1996 Feb;81(2):783-90. doi: 10.1210/jcem.81.2.8636304.
Activin, a member of the transforming growth factor-beta (TGF beta) cytokine family, acts as a pituitary cell mitogen via a novel family of receptor-linked serine/threonine (Ser/Thr) kinases. Pituitary tumors synthesize activin subunits, and the autocrine action of these growth factors may modulate tumor proliferation. We, therefore, investigated the expression of activin/TGF beta type I receptor messenger ribonucleic acids (mRNAs), designated ALK1 through ALK5 (ALK = activin receptor-like kinase), and type II receptor mRNAs using RT-PCR in 34 human pituitary adenomas of all phenotypes and normal pituitary tissue. ALK2 and ALK5, specific mediators of activin and TGF beta signals, respectively, were found to be expressed only in tumor and not in normal pituitary cells, and ALK2 expression was found only in tumors of a mammosomatotroph cell lineage. ALK1, ALK3, and ALK4 mRNAs were found in both normal and neoplastic pituitary cells. The alternatively spliced cytoplasmic domain of ALK4 consists of 11 kinase subdomains, that are critical for modulating receptor function and intracellular signaling. Truncated forms of the ALK4 cytoplasmic domain lacking these subdomains may attenuate activin signal transduction and affect both tumor phenotype and proliferation via the formation of inactive type I/type II complexes. Three truncated ALK4 receptor mRNAs generated by alternate splicing of the cytoplasmic Ser/Thr kinase domain were found to be tumor specific. One of these truncated receptor mRNAs, ALK4-5, is a novel splice variant that has not been previously described. Expression of the ActRII and T beta RII type II receptor mRNAs, which specifically bind activin and TGF beta, respectively, was highly prevalent among all tumor subtypes and normal pituitary tissue. However, ActRIIB, an activin-specific type II receptor that displays a 3- to 4-fold higher affinity for ligand than ActRII, was expressed in 94% of tumors, but was not prevalent in normal tissue. These data are the first to demonstrate tumor-specific expression of Ser/Thr kinase receptors mRNAs and their splice variants in human pituitary adenomas.
激活素是转化生长因子-β（TGF-β）细胞因子家族的成员，它通过一类新的受体连接丝氨酸/苏氨酸（Ser/Thr）激酶作为垂体细胞有丝分裂原。垂体肿瘤合成激活素亚基，这些生长因子的自分泌作用可能调节肿瘤增殖。因此，我们使用逆转录聚合酶链反应（RT-PCR）研究了激活素/TGF-β I型受体信使核糖核酸（mRNA）（命名为ALK1至ALK5，ALK=激活素受体样激酶）和II型受体mRNA在34例各种表型的人垂体腺瘤及正常垂体组织中的表达。分别作为激活素和TGF-β信号特异性介质的ALK2和ALK5，仅在肿瘤中表达，而在正常垂体细胞中不表达，且ALK2表达仅见于乳腺生长激素细胞系的肿瘤中。ALK1、ALK3和ALK4 mRNA在正常和肿瘤性垂体细胞中均有发现。ALK4可变剪接的胞质结构域由11个激酶亚结构域组成，这些亚结构域对调节受体功能和细胞内信号传导至关重要。缺乏这些亚结构域的ALK4胞质结构域截短形式可能会减弱激活素信号转导，并通过形成无活性的I型/II型复合物影响肿瘤表型和增殖。通过胞质Ser/Thr激酶结构域的可变剪接产生的三种截短的ALK4受体mRNA被发现具有肿瘤特异性。其中一种截短的受体mRNA，ALK4-5，是一种以前未描述过的新型剪接变体。分别特异性结合激活素和TGF-β的ActRII和TβRII II型受体mRNA的表达在所有肿瘤亚型和正常垂体组织中都非常普遍。然而，ActRIIB，一种对配体的亲和力比ActRII高3至4倍的激活素特异性II型受体，在94%的肿瘤中表达，但在正常组织中不普遍。这些数据首次证明了Ser/Thr激酶受体mRNA及其剪接变体在人垂体腺瘤中的肿瘤特异性表达。
