Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system

Abstract

The 2;5 chromosomal translocation is frequently associated with anaplastic large cell lymphomas (ALCLs). The translocation creates a fusion gene consisting of the alk (anaplastic lymphoma kinase) gene and the nucelophosmin (npm) gene: the 3' half of alk derived from chromosome 2 is fused to the 5' portion of npm from chromosome 5. A recent study shows that the product of the npm-alk fusion gene is oncogenic. To help understand how the npm-alk oncogene transform cells, it is important to investigate the normal biological function of the alk gene product, ALK. Here, we show molecular cloning of cDNAs for both the human and mouse ALK proteins. The deduced amino acid sequences reveal that ALK is a novel receptor protein-tyrosine kinase having a putative transmembrane domain and an extracellular domain. These sequences are absent in the product of the transforming npm-alk gene. ALK shows the greatest sequence similarity to LTK (leukocyte tyrosine kinase) whose biological function is presently unknown. RNA blot hybridization analysis of various tissues reveals that the alk mRNA is dominantly detected in the brain and spinal cord. Immunoblotting with anti-ALK antibody shows that ALK is highly expressed in the neonatal brain. Furthermore, RNA in situ hybridization analysis shows that the alk mRNA is dominantly expressed in neurons in speci®c regions of the nervous system such as the thalamus, mid-brain, olfactory bulb, and ganglia of embryonic and neonatal mice. These data suggest that ALK plays an important role(s) in the development of the brain and exerts its e ects on speci®c neurons in the nervous system.

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…Nucleophosmin allows dimerization of the fusion protein, causing constitutive activation of ALK kinase and downstream activation of phospholipase C-g, PI3K, STATs and pp60c-src (Allouche, 2007). The native full-length ALK receptor is mainly expressed in discrete regions of the developing central and peripheral nervous system (Iwahara et al, 1997). Mourali et al (2006) forced ALK expression in cells of lymphoid and neuronal origin to investigate wild-type ALK functions.…”

Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer

“…ALK is functionally important in embryonic development [3] and in determination of cell survival and cell fate [4]. However, ALK was originally discovered when it was found that the chimeric N-terminal nucleophosmin (NPM) domain/cytoplasmic (catalytic) ALK domain fusion protein (NPM-ALK) is the oncoprotein underlying the pathogenesis of anaplastic large cell lymphomas (ALCL) [5,6].…”

Recruitment of insulin receptor substrate-1 and activation of NF-κB essential for midkine growth signaling through anaplastic lymphoma kinase

“…Subsequent studies identified several other ALK kinase fusion proteins that support oncogenesis (Hernandez et al, 1999;Colleoni et al, 2000;Lawrence et al, 2000;Ma et al, 2000;Touriol et al, 2000;Trinei et al, 2000). Full-length ALK was initially described as an orphan receptor tyrosine kinase that shows restricted tissue distribution and is regulated during organ development (Iwahara et al, 1997;Morris et al, 1997). Several studies show expression of full-length ALK protein in cultured fibroblasts and endothelial cells as well as cell lines derived from epithelial cancers such as pancreatic and breast carcinoma (Stoica et al, 2001 and the neuroectoderm, that is, melanoma (Dirks et al, 2002), neuroblastoma Stoica et al, 2002) glioblastoma and non-Hodgkin's lymphoma (Delsol et al, 1997), reviewed by Pulford et al (2004).…”