Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that was first identified in anaplastic large cell lymphoma (ALCL) as part of the fusion protein NPM-ALK. ALK is highly expressed throughout the central and peripheral nervous system during development, with levels decreasing following gestation. Low levels of ALK protein are however, expressed in the adult CNS, whilst ALK transcripts have also been identified in the periphery.
The physiological role of ALK has yet to be determined, although due to its expression profile it has been postulated to be involved in neuronal differentiation. ALK has two putative endogenous ligands, midkine (MK) and leiotrophin (PTN), which have both been implicated in neurite growth and have similar expression profiles to ALK. Ligand binding to ALK initiates homodimerization and autophosphorylation of the three tyrosine residues within the kinase domain, which results in tyrosine kinase activation. Downstream effectors of ALK tyrosine kinase activity have been shown to include the Ras-ERK, PI 3-K-Akt, JAK-STAT and NF-κB signaling pathways. In the absence of ligand binding ALK is inactive, with its expression promoting apoptosis. Conversely, when ALK is activated through either ligand binding or as part of an ALK fusion protein, apoptosis is decreased.
The expression of many ALK fusion oncogenes have been implicated in the pathogenesis of many types of cancer. Examples include NPM-ALK, EML4-ALK and CLTLC-ALK which have been described in ALCL, non-small cell lung cancer (NSCLC) and diffuse large B cell lymphoma (DLBCL) respectively. ALK fusion proteins consist of a C-terminus composed of the intracellular tyrosine kinase domain of ALK and an N-terminus derived from the partner protein. The partner protein has been shown to induce constitutive kinase activation by mediating ALK dimerization. ALK is also involved in oncogenesis through overexpression and gain-of-function mutations. ALK is overexpressed in NSCLC, melanoma and certain types of breast cancer, amongst others, whilst point mutations in the ALK kinase domain have been implicated in neuroblastoma development.
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Literature for ALK
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