Molecular characterization of WDCP, a novel fusion partner for the anaplastic lymphoma tyrosine kinase ALK

Yokoyama,Noriko; Miller,W.  Todd

doi:10.3892/br.2014.374

Molecular characterization of WDCP, a novel fusion partner for the anaplastic lymphoma tyrosine kinase ALK

Authors:
- Noriko Yokoyama
- W. Todd Miller
View Affiliations

Affiliations: Department of Physiology and Biophysics, School of Medicine, State University of New York at Stony Brook, Stony Brook, NY 11794, USA
Published online on: November 3, 2014 https://doi.org/10.3892/br.2014.374
Pages: 9-13

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Anaplastic lymphoma kinase (ALK) is a member of the receptor tyrosine kinase superfamily. The ALK gene is a site of frequent mutation and chromosomal rearrangement in various types of human cancers. A novel chromosomal translocation was recently identified in human colorectal cancer between the ALK gene and chromosome 2, open reading frame 44 (C2orf44), a gene of unknown function. As a first step in understanding the oncogenic properties of this fusion protein, C2orf44 cDNA was cloned and the encoded protein was characterized, which was designated as WD repeat and coiled coil containing protein (WDCP). A C‑terminal proline‑rich segment in WDCP was shown to mediate binding to the Src homology 3 domain of the Src family kinase hematopoietic cell kinase (Hck). Co‑expression with Hck lead to tyrosine phosphorylation of WDCP. Chromatographic fractionation of WDCP‑containing lysates indicates that the protein exists as an oligomer in mammalian cells. These results suggest that, in the context of the ALK‑C2orf44 gene fusion, WDCP imposes an oligomeric structure on ALK that results in constitutive kinase activation and signaling.

View Figures

View References

1	Futreal PA, Coin L, Marshall M, et al: A census of human cancer genes. Nat Rev Cancer. 4:177–183. 2004. View Article : Google Scholar
2	Pleasance ED, Cheetham RK, Stephens PJ, et al: A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 463:191–196. 2010. View Article : Google Scholar : PubMed/NCBI
3	Pleasance ED, Stephens PJ, O'Meara S, et al: A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. 463:184–190. 2010. View Article : Google Scholar : PubMed/NCBI
4	Greenman C, Stephens P, Smith R, et al: Patterns of somatic mutation in human cancer genomes. Nature. 446:153–158. 2007. View Article : Google Scholar : PubMed/NCBI
5	Lipson D, Capelletti M, Yelensky R, et al: Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 18:382–384. 2012. View Article : Google Scholar : PubMed/NCBI
6	Chiarle R, Voena C, Ambrogio C, Piva R and Inghirami G: The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 8:11–23. 2008. View Article : Google Scholar : PubMed/NCBI
7	Shackelford RE, Vora M, Mayhall K and Cotelingam J: ALK-rearrangements and testing methods in non-small cell lung cancer: a review. Genes Cancer. 5:1–14. 2014.PubMed/NCBI
8	Morales La Madrid A, Campbell N, Smith S, Cohn SL and Salgia R: Targeting ALK: a promising strategy for the treatment of non-small cell lung cancer, non-Hodgkin's lymphoma, and neuroblastoma. Target Oncol. 7:199–210. 2012.PubMed/NCBI
9	Hallberg B and Palmer RH: Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat Rev Cancer. 13:685–700. 2013. View Article : Google Scholar : PubMed/NCBI
10	Morris SW, Kirstein MN, Valentine MB, et al: Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science. 263:1281–1284. 1994. View Article : Google Scholar
11	Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 448:561–566. 2007. View Article : Google Scholar : PubMed/NCBI
12	Scott MP, Zappacosta F, Kim EY, Annan RS and Miller WT: Identification of novel SH3 domain ligands for the Src family kinase Hck. Wiskott-Aldrich syndrome protein (WASP), WASP-interacting protein (WIP), and ELMO1. J Biol Chem. 277:28238–28246. 2002. View Article : Google Scholar : PubMed/NCBI
13	UniProt Consortium, . Activities at the Universal Protein Resource (UniProt). Nucleic Acids Res. 42:(Database issue). D191–D198. 2014.PubMed/NCBI
14	Smith TF, Gaitatzes C, Saxena K and Neer EJ: The WD repeat: a common architecture for diverse functions. Trends Biochem Sci. 24:181–185. 1999. View Article : Google Scholar : PubMed/NCBI
15	Mayer BJ and Eck MJ: SH3 domains. Minding your p's and q's. Curr Biol. 5:364–367. 1995. View Article : Google Scholar : PubMed/NCBI
16	Nguyen JT, Porter M, Amoui M, Miller WT, Zuckermann RN and Lim WA: Improving SH3 domain ligand selectivity using a non-natural scaffold. Chem Biol. 7:463–473. 2000. View Article : Google Scholar : PubMed/NCBI
17	Bilsland JG, Wheeldon A, Mead A, et al: Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications. Neuropsychopharmacology. 33:685–700. 2008. View Article : Google Scholar
18	Soda M, Takada S, Takeuchi K, et al: A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci USA. 105:19893–19897. 2008. View Article : Google Scholar : PubMed/NCBI
19	Cussac D, Greenland C, Roche S, et al: Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity. Blood. 103:1464–1471. 2004. View Article : Google Scholar : PubMed/NCBI