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ALK, the Chromosome 2 Gene Locus Altered by the T(2;5) in Non Oncogene (1997) 14, 2175 ± 2188 1997 Stockton Press All rights reserved 0950 ± 9232/97 $12.00 ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK) Stephan W Morris1,2,4, Clayton Naeve3, Prasad Mathew5, Payton L James1, Mark N Kirstein1, Xiaoli Cui1 and David P Witte6,7 Departments of 1Experimental Oncology, 2Hematology-Oncology and 3Virology and Molecular Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105; 4Department of Pediatrics, University of Tennessee College of Medicine, Memphis, Tennessee 38163; 5Department of Pediatrics, Medical College of Ohio, Toledo, Ohio 43699; 6Department of Pathology, University of Cincinnati College of Medicine and 7Division of Pathology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA Anaplastic Lymphoma Kinase (ALK) was originally Introduction identi®ed as a member of the insulin receptor subfamily of receptor tyrosine kinases that acquires transforming Diverse cellular processes such as division, differentia- capability when truncated and fused to nucleophosmin tion, survival, metabolism, and motility can all be (NPM) in the t(2;5) chromosomal rearrangement regulated through binding of cognate ligands to their associated with non-Hodgkin's lymphoma, but further speci®c receptor tyrosine kinases (RTKs) (reviewed in insights into its normal structure and function are Schlessinger and Ullrich, 1992; Fantl et al., 1993). The lacking. Here, we characterize a full-length normal common structural features of the RTKs include an human ALK cDNA and its product, and determine the extracellular ligand-binding region, a hydrophobic pattern of expression of its murine homologue in membrane-spanning segment and a cytoplasmic do- embryonic and adult tissues as a ®rst step toward the main that carries the catalytic function. In general, the functional assessment of the receptor. Analysis of the activation of these molecules to initiate signal 6226 bp ALK cDNA identi®ed an open reading frame transduction involves ligand-mediated receptor dimer- encoding a 1620-amino acid (aa) protein of predicted ization and intermolecular transphosphorylation, which mass *177 kDa that is most closely related to begins a phosphorylation cascade through the binding leukocyte tyrosine kinase (LTK), the two exhibiting of SH2 or PTB domains of cellular substrates to 57% aa identity and 71% similarity over their region of speci®c receptor phosphotyrosine residues (Mayer and overlap. Biochemical analysis demonstrated that the Baltimore, 1993; Schlessinger, 1994; van der Geer and *177 kDa ALK polypeptide core undergoes co-transla- Pawson, 1995). Dysregulation of this process either at tional N-linked glycosylation, emerging in its mature the level of the receptor or aecting key elements of the form as a 200 kDa single chain receptor. Surface signaling cascade has been shown to result in a variety labeling studies indicated that the 200 kDa glycoprotein of neoplastic disorders or in altered development. For is exposed at the cell membrane, consistent with the example, structural rearrangement of RTK genes, as prediction that ALK serves as the receptor for an seen with TRKA, MET and RET, has been shown to unidenti®ed ligand(s). In situ hybridization studies activate the transforming capacity of the proteins they revealed Alk expression beginning on embryonic day encode, contributing to the genesis of human tumors 11 and persisting into the neonatal and adult periods of (Martin-Zanca et al., 1986; Soman et al., 1991; Greco development. Alk transcripts were con®ned to the et al., 1992; Bongarzone et al., 1993). nervous system and included several thalamic and A number of studies have now demonstrated that hypothalamic nuclei; the trigeminal, facial, and acoustic RTKs normally function to regulate the cellular cranial ganglia; the anterior horns of the spinal cord in growth and dierentiation of speci®c tissues or the region of the developing motor neurons; the organs. For example, the TRK gene family (TRK-A, - sympathetic chain; and the ganglion cells of the gut. B and -C) encodes receptors for the neurotrophic Thus, ALK is a novel orphan receptor tyrosine kinase ligands nerve growth factor, brain-derived neuro- that appears to play an important role in the normal trophic factor, neurotrophin-3 and neurotrophin-4 development and function of the nervous system. (Barbacid, 1993). Targeting experiments in mice have demonstrated that functional inactivation of the TRK Keywords: anaplastic lymphoma kinase (ALK); recep- genes produces multiple abnormalities of the central tor tyrosine kinase; neural-speci®c; leukocyte tyrosine and peripheral nervous systems (Snider, 1994). The kinase (LTK); chromosome 2 MET RTK has been shown to be the cell surface receptor for hepatocyte growth factor (HGF)/scatter factor (SF), which mediates liver development and regeneration (Bottaro et al., 1991; Naldini et al., 1991) and provides a signal for the migration of skeletal muscle precursor cells from the somites to the Correspondence: SW Morris developing limbs and diaphragm (Bladt et al., 1995). Received 23 October 1996; revised 23 January 1997; accepted With increasing frequency, the normal functional role 24 January 1997 of RTKs is also being elucidated because of their ALK, a novel, neural receptor tyrosine kinase SW Morris et al 2176 identi®cation as disease genes. Recent examples include phosphoprotein nucleophosmin (NPM), a highly the identi®cation of RET mutations that lead to the conserved RNA-binding nucleolar protein (Borer et loss of enteric innervation in Hirschsprung's disease al., 1989; Chan et al., 1989; Dumbar et al., 1993), (congenital megacolon) or to tumor formation in linked to the cytoplasmic portion of a novel receptor multiple endocrine neoplasia type IIB (van Heynin- tyrosine kinase encoded on chromosome 2 which we gen, 1994), and the causal association between named Anaplastic Lymphoma Kinase (ALK). Here, mutations within ®broblast growth factor receptor we describe the isolation and sequence analysis of a (FGFR) family members and the congenital malforma- full-length normal human ALK receptor cDNA, tions Pfeier syndrome (craniosynostosis, cutaneous demonstrating that ALK is a member of the insulin syndactyly and short, broad digits) (FGFR1) (Muenke receptor subfamily of RTKs with closest homology to et al., 1994), Apert and Crouzon syndromes (cranio- leukocyte tyrosine kinase (LTK) (Ben-Neriah and synostosis with or without syndactyly of the hands and Bauskin, 1988; Bernards and de la Monte, 1990; feet) (FGFR2) (Wilkie et al., 1995) and achondroplasia Maru et al., 1990; Krolewski and Dalla-Favera, 1991; (short-limbed dwar®sm and macrocephaly) (FGFR3) Snijders et al., 1993; Toyoshima et al., 1993; (Rousseau et al., 1994). Kozutsumi et al., 1994). Biochemical characterization We have recently described the positional cloning of the ALK polypeptide encoded by this cDNA, and and characterization of the t(2;5)(p23;q35) chromoso- of the receptor protein produced endogenously by mal rearrangement found in approximately 10% of all rhabdomyosarcoma skeletal muscle tumor cells, non-Hodgkin's lymphomas (Morris et al., 1994). This reveals that ALK is a large, glycosylated, single translocation produces a fusion gene that encodes a chain transmembrane receptor tyrosine kinase. In situ chimeric transforming protein comprised of the hybridization studies of mouse embryos and adult amino-terminal portion of the chromosome 5-encoded mouse organs indicate that the expression of the Figure 1 Schematic representation (a) and deduced amino acid sequence (b) of a human ALK cDNA clone. (a) The thick bar represents the coding sequences of the 6226 bp insert of human ALK cDNA clone RMS17-2. The putative signal peptide (SP, hatched box), transmembrane (TM, solid box), and tyrosine kinase (TK, stippled box) domains are indicated. Cysteine residues (solid circles) and consensus N-glycosylation sites (inverted triangles) present in the extracellular domain are indicated. The thin open bars on either end represent 5' and 3' non-coding sequences. (b) Deduced amino acid sequence encoded by ALK cDNA clone RMS17-2. The putative signal peptide (amino acids 1 ± 26) is underlined. Cysteine residues within the extracellular domain are circled. Consensus N-glycosylation sites (N-X-S/T) are enclosed by open boxes. The transmembrane domain (residues 1031 ± 1058) is highlighted by a hatched box. Horizontal arrows ¯ank the tyrosine kinase catalytic domain (residues 1123 ± 1376). The amino- terminal and carboxy-terminal extent of the overlap of the largest reported receptor isoform of human LTK (Toyoshima et al., 1993) with ALK is indicated. The position at which ALK is truncated by the t(2;5) to produce NPM-ALK is also shown (`NPM- ALK fusion junction') ALK, a novel, neural receptor tyrosine kinase SW Morris et al 2177 homologue, Alk, is restricted to the nervous system, extracellular domain of ALK after signal peptide suggesting that the receptor binds a ligand(s) critical cleavage is 1004 amino acids long and is followed by for neural development and function. 28 hydrophobic amino acids, consistent with a membrane-spanning segment. This single putative transmembrane domain is ¯anked on its cytoplasmic side by basic amino acid residues typical of the Results junction between transmembrane and cytoplasmic domains (Blobel, 1980). Within the extracellular Cloning and characterization of a full-length
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