%0 Journal Article
%T NPM-ALK: The Prototypic Member of a Family of Oncogenic Fusion Tyrosine Kinases
%A Joel D. Pearson
%A Jason K. H. Lee
%A Julinor T. C. Bacani
%A Raymond Lai
%A Robert J. Ingham
%J Journal of Signal Transduction
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/123253
%X Anaplastic lymphoma kinase (ALK) was first identified in 1994 with the discovery that the gene encoding for this kinase was involved in the t(2;5)(p23;q35) chromosomal translocation observed in a subset of anaplastic large cell lymphoma (ALCL). The NPM-ALK fusion protein generated by this translocation is a constitutively active tyrosine kinase, and much research has focused on characterizing the signalling pathways and cellular activities this oncoprotein regulates in ALCL. We now know about the existence of nearly 20 distinct ALK translocation partners, and the fusion proteins resulting from these translocations play a critical role in the pathogenesis of a variety of cancers including subsets of large B-cell lymphomas, nonsmall cell lung carcinomas, and inflammatory myofibroblastic tumours. Moreover, the inhibition of ALK has been shown to be an effective treatment strategy in some of these malignancies. In this paper we will highlight malignancies where ALK translocations have been identified and discuss why ALK fusion proteins are constitutively active tyrosine kinases. Finally, using ALCL as an example, we will examine three key signalling pathways activated by NPM-ALK that contribute to proliferation and survival in ALCL. 1. The ALK Receptor Tyrosine Kinase Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase of the insulin receptor superfamily, and in mice and humans, the normal expression of ALK is largely restricted to the brain and nervous system [1¨C4]. Mice deficient in ALK appear to have no overt developmental abnormalities [5¨C8]; however, behavioural abnormalities have been noted in these mice. ALK-deficient mice perform better on tests of cognitive ability and display less anxiety than their wild-type littermate controls [6, 7]. Behavioural tests also demonstrated increased alcohol consumption and altered sensitivity to alcohol in ALK-deficient mice compared to wild-type littermates [8]. Intriguingly, single-nucleotide polymorphisms (SNPs) in ALK have been identified in humans that correlate with decreased response to alcohol [8]. A correlation between ALK SNPs and schizophrenia has also been noted in a Japanese study [9]. In Drosophila melanogaster, the jelly belly protein (Jeb) has been characterized as an ALK ligand [10¨C12]. In mammals, there does not appear to be a Jeb homologue but two ligands for ALK have been described, pleiotrophin [13] and midkine [14]. However, there is not complete agreement regarding whether these are indeed ALK stimulating ligands [15, 16]. More recently, Perez-Pinera and colleagues proposed an
%U http://www.hindawi.com/journals/jst/2012/123253/