Morris S W, Naeve C, Mathew P, James P L, Kirstein M N, Cui X, Witte D P
Department of Experimental Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Oncogene. 1997 May 8;14(18):2175-88. doi: 10.1038/sj.onc.1201062.
Anaplastic Lymphoma Kinase (ALK) was originally identified as a member of the insulin receptor subfamily of receptor tyrosine kinases that acquires transforming capability when truncated and fused to nucleophosmin (NPM) in the t(2;5) chromosomal rearrangement associated with non-Hodgkin's lymphoma, but further insights into its normal structure and function are lacking. Here, we characterize a full-length normal human ALK cDNA and its product, and determine the pattern of expression of its murine homologue in embryonic and adult tissues as a first step toward the functional assessment of the receptor. Analysis of the 6226 bp ALK cDNA identified an open reading frame encoding a 1620-amino acid (aa) protein of predicted mass approximately 177 kDa that is most closely related to leukocyte tyrosine kinase (LTK), the two exhibiting 57% aa identity and 71% similarity over their region of overlap. Biochemical analysis demonstrated that the approximately 177 kDa ALK polypeptide core undergoes co-translational N-linked glycosylation, emerging in its mature form as a 200 kDa single chain receptor. Surface labeling studies indicated that the 200 kDa glycoprotein is exposed at the cell membrane, consistent with the prediction that ALK serves as the receptor for an unidentified ligand(s). In situ hybridization studies revealed Alk expression beginning on embryonic day 11 and persisting into the neonatal and adult periods of development. Alk transcripts were confined to the nervous system and included several thalamic and hypothalamic nuclei; the trigeminal, facial, and acoustic cranial ganglia; the anterior horns of the spinal cord in the region of the developing motor neurons; the sympathetic chain; and the ganglion cells of the gut. Thus, ALK is a novel orphan receptor tyrosine kinase that appears to play an important role in the normal development and function of the nervous system.
间变性淋巴瘤激酶（ALK）最初被鉴定为受体酪氨酸激酶胰岛素受体亚家族的成员，在与非霍奇金淋巴瘤相关的t(2;5)染色体重排中，当它被截断并与核磷蛋白（NPM）融合时获得转化能力，但对其正常结构和功能的进一步认识尚缺。在此，我们鉴定了全长正常人类ALK cDNA及其产物，并确定其小鼠同源物在胚胎和成年组织中的表达模式，作为对该受体进行功能评估的第一步。对6226 bp的ALK cDNA分析确定了一个开放阅读框，编码一个预测分子量约为177 kDa的1620个氨基酸（aa）的蛋白质，该蛋白质与白细胞酪氨酸激酶（LTK）关系最为密切，二者在重叠区域表现出57%的氨基酸同一性和71%的相似性。生化分析表明，约177 kDa的ALK多肽核心进行共翻译N-连接糖基化，以200 kDa单链受体的成熟形式出现。表面标记研究表明，200 kDa糖蛋白暴露于细胞膜，这与ALK作为未鉴定配体受体的预测一致。原位杂交研究显示，Alk表达从胚胎第11天开始，并持续到新生儿期和成年发育期。Alk转录本局限于神经系统，包括几个丘脑和下丘脑核；三叉神经、面神经和听神经颅神经节；发育中运动神经元区域的脊髓前角；交感神经链；以及肠道神经节细胞。因此，ALK是一种新型孤儿受体酪氨酸激酶，似乎在神经系统的正常发育和功能中发挥重要作用。
