ALK

ALK

Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ALK gene. ALK plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system.

One promising new avenue for targeted therapy of neuroblastoma focuses on anaplastic lymphoma kinase (ALK), a cell-surface neural receptor tyrosine kinase (RTK) expressed at significant levels only in the developing embryonic and neonatal brain. Receptor tyrosine kinases (RTKs) are a class of protein molecules that play crucial roles in the development of multicellular organisms. Aberrations in RTK function lead to both developmental defects and cancer. These receptors function at the cell surface, bind extracellular growth factors/ligands, and transmit a molecular message through the plasma membrane to intracellular machinery that then spread the signal to induce global changes on the cellular level. These types of signals include induction of growth, survival, and proliferation. Proper spatial and temporal action of these receptors and their cognate ligands is essential to the development of an organism.

ALK was first discovered in 1994 as part of an oncogenic product found in patients with anaplastic large-cell lymphoma (ALCL), a non-Hodgkin’s lymphoma. In ALCL, an oligomerizing protein called nucleophosmin (NPM) is fused to ALK, and the fusion results in constitutive activation of the kinase domain of ALK. In 2007, ALK was also implicated in a subset of non-small cell lung cancer (NSCLC) as part of another oncogenic fusion protein with constitutive kinase activity. In both ALCL and NSCLC, the cancerous cells were dependent on ALK for proliferation. ALK has since been linked to many cancers, including esophageal squamous cell carcinoma, adult and pediatric renal cell carcinomas, colonic adenocarcenomas, anaplastic thyroid cancer, and others. Consequently, ALK has been thrust into the limelight of cancer research.

As a classical RTK, the full length ALK receptor is composed of an ECD, a single transmembrane domain, and a cytoplasmic domain. Together with another RTK member, Leukocyte Tyrosine Kinase (LTK), ALK constitutes a subfamily of RTKs; the ECDs of both LTK and ALK contain a unique glycine rich domain (GlyR) and an EGF-like motif. In addition, the ECD of ALK also has an N-terminal domain (NTR), and two MAM domains separated by an LDL-A domain. There is a conserved, highly basic 249 amino acid N-terminal region (NTR) in vertebrate ALKs. The NTR of ALK has no reported function and is not conserved among invertebrate ALKs or found in any other protein.

The orphan receptor ALK was originally identified in anaplastic large-cell non-Hodgkin’s lymphoma as an oncogenic fusion protein with Nucleophosmin (NPM) resulting from a 2;5 chromosomal translocation. The ALK gene is a hotspot for a variety of chromosomal translocations that result in the formation of fusion proteins that undergo spontaneous dimerization leading to constitutive activation of the ALK kinase domain. These chimeric ALK proteins were shown to drive numerous human cancers, both in hematopoietic malignancies and in solid tumors. The two most prevalently cited fusion proteins among more than 40 observed ALK fusions are NPMALK and EML4-ALK.

In contrast to ALK fusion proteins, full-length, non-chimeric ALK is a driver of neuroblastoma (NBL) where genetic studies have identified it as a major target of genetic alterations such as gene amplification and somatic and germ line mutations. The majority of missense mutations in ALK found in NBL are located in the kinase domain and lead to constitutive receptor activation. Amplification of ALK and co-amplification with MYCN (both genes are located on chromosome 2p) drive and cooperate in NBL progression.

Reference:Phillip Bradley Murray. Discovery and Characterization of Ligands for the Receptor Tyrosine Kinase ALK: AUG-aipha, AUG-beta and Heparin

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