Identifier: R-HSA-9700179
The ALK locus is subject to chromosomal translocations and inversions that give rise to oncogenic fusion proteins in a number of different cancers. To date, ALK has been identified as a fusion partner with more than 25 proteins in cancers ranging from anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), diffuse B-cell lymphoma, neuroblastoma, rhabdomyosarcoma and inflammatory myofibroblastic tumors, among others (reviewed in Roskoski, 2013; Della Corte et al, 2018). These fusion proteins form constitutive, ligand-independent dimers by virtue of an N-terminal dimerization domain contributed by the fusion partner, and retain the intracellular region of the ALK receptor tyrosine kinase. Expression (and often overexpression) of the fusion proteins is regulated by the promoter of the fusion partner. Signaling downstream of the fusion proteins occurs through numerous pathways including the MAP kinase, PI3K and STAT cascades, among others, but the extent to which each pathway is activated downstream of the different fusions varies (Armstrong et al, 2004; reviewed in Hallberg and Palmer, 2013; Hallberg and Palmer, 2016; Della Corte et al, 2018, Roskoski, 2013).
The best characterized ALK fusion protein is NPM-ALK, which occurs in 75-80% of ALCLs, and fuses the intracellular portion of ALK with the N-terminal region of nucleophosmin, a protein involved in DNA repair, transcription and genome stability. NPM-ALK constitutively dimerizes based on the N-terminal NPM region. Deletion of the N-terminal domain abrogates oligomerization and abolishes the transformation activity of the protein (Morris et al, 1995; Fujimoto et al, 1996).
In addition to NPM, fusions with ALK have also been identified with EML4 (Soda et al, 2007; Choi et al, 2008; Takezawa et al, 2011), CLTC (De Paepe et al, 2003; Cherchetti et al, 2011; Chiakatsu et al, 2003), TPM3 (Lamant et al, 1999; Lawrence et al, 2000), TPM4 (Lawrence et al, 2000), RANBP2 (Marino-Enriquez et al, 2011a; Lee et al, 2017; Chen et al, 2008), STRN (Majewska et al, 2013; Perot et al, 2014; Kelly et al, 2014), ATIC (Colleoni et al, 2000; Trinei et al, 2000; Ma et al, 2000), KIF5B (Wong et al, 2011), TFG (Hernandez et al, 1999; Hernandez et al, 2002), HIP1 (Ou et al, 2014; Hong et al, 2014; Fang et al, 2014), CARS1 (Cools et al, 2002; Debelenko et al, 2003), PPF1BP1 (Takeuchi et al, 2011; Yoshida et al, 2013), MSN (Tort et al, 2001), VCL (Marino-Enriquez et al, 2011b; Debelenko et al, 2011), KLC1 (Togayashi et al, 2012), SEC31A (Panagopoulos et al, 2006), SQSTM1 (Iyevleva et al, 2015; Takeuchi et al, 2011), TPR (Choi et al, 2014), WDCP (Lipson et al, 2012), RRBP1 (Lee et al, 2017), DCTN1 (Subbiah et al, 2015; Lee et al, 2017; Iyevleva et al, 2015; Wang et al, 2012; Wiesner et al, 2014), EEF1A (van der Krogt et al, 2017), BIRC6 (Shan et al, 2015), EIF2AK3 (Ali et al, 2016), PPM1B (Ali et al, 2016), PRKAR1A (Ali et al, 2016), GCC2 (Noh et al, 2017), BCL11A (Tian et al, 2007) and LMO7 (Noh et al, 2017).