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Contents 1 Anaplastic Lymphoma Kinase (ALK) 1.1 Introduction 1.2 General Structure 1.2.1 Ligand Binding 1.2.1.1 Tyrosine Phosphorylation Mechanism 1.3 Applications

Anaplastic Lymphoma Kinase (ALK)

Introduction

Anaplastic lymphoma kinase is a receptor tyrosine kinase (RTK) that is important in regulating functions within the central nervous system ^[1]. RTKs are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. The route to discovery of this protein's structure was rather complex, spanning almost 20 years; the kinase domain was discovered in 1994, the full protein structure in 1997, and the ligand structures in 2014. These structures were found using cryo-electron microscopy,nuclear magnetic resonance, and X-ray crystallography. Anaplastic lymphoma kinase is a proto-oncogene with mutations associated with various types of cancers, including non-small-cell lung cancer, anaplastic large cell lymphoma, squamous cell carcinoma, and inflammatory myofibroblastic cancer ^[2]. ALK is a referred to as a proto-oncogene because certain mutations in it's protein sequence are known to have a strong positive association with the development of cancerous cells.

General Structure

Anaplastic lymphoma kinase is a , each monomer consisting of seven domains and two regions ^[3]. These domains and regions are as follows: N-terminal region (NTR), two meprin–A-5 protein–receptor protein tyrosine phosphatase μ domains (MAM), low density lipoprotein receptor class A domain (LDL), (TNF), (GlyR), (EGF), transmembrane α-helix (TMH), kinase domain ^[1]. The structures of the N-terminal region, MAM, and LDL have not been determined. The glycine rich region is a part of the TNF domain. Only the TNF, GlyR, and EGF portions of ALK are required for ligand binding. All portions of anaplastic lymphoma kinase are located in the extracellular domain except for the transmembrane α-helix which is in the transmembrane region and the kinase domain that is located in the intracellular region.

Ligand Binding

The ligands recognized by anaplastic lymphoma kinase are FAM150 in a monomeric fashion and in a dimeric fashion. It's biologically preferred ligand is dimeric AUG. The binding of ALK to it's ligand results in homodimerization and a conformational change. Prior to the ligand binding to anaplastic lymphoma kinase, the extracellular domain is oriented vertically and perpendicularly to the plasma membrane. Once the ligand is , ALK undergoes a conformational change and folds over so that the positively charged residues on the portion of the protein previously oriented vertically is now interacting with the negatively charged residues on the plasma membrane. The residues of ALK and it's ligand interact through the formation of . This conformational change via ligand binding induces the auto-activation of the kinase domain, in which the domains use the tyrosine phosphorylation mechanism to phosphorylate tyrosine residues on the opposite monomer.

Tyrosine Phosphorylation Mechanism

Dimerization of anaplastic lymphoma kinase activates the kinase domains of each monomer. Next, the kinase domains phosphorylate the tyrosine residues of the opposite monomer using ATP. These phosphorylated tyrosine residues recruit signal proteins through phosphorylation. These signal proteins begin a signaling cascade through utilizing various signal pathways. These pathways signal for cell proliferation and survival (ex: begin transcription).

Applications

Anaplastic lymphoma kinase's involvement as a proto-oncogene in various types of cancers has made it a target for drug therapies for these types of cancers ^[4]. These treatments are utilized on the basis that overactivation of the kinase domain of ALK by ATP binding is causing the cells to send out growth signals more rapidly than usual. This over expression of growth signals allows the cancer cells to grow more rapidly than our normal cells. One therapeutic medication that has been increasingly used with high levels of success is . This medication was approved by the FDA in January of 2021 for the treatment of pediatric/young adult ALK-positive anaplastic large cell lymphoma. ALK-positive cancers are those in which the individual has an oncogenic mutation in their ALK protein sequence that is contributing to the proliferation of the cancer cells. The treatment has an overall response rate of 90%. Crizotinib works by to the ATP binding site of the ^[5]. Crizotinib binds preferentially to ATP in this region and therefore can effectively block the binding of ATP ^[5]. With the binding of ATP being blocked, the intercellular signaling cascade cannot begin which works to prevent cancerous cells from growing and spreading . Crizotinib also potently inhibits the RTK, cMET, due to it's kinase domain ATP binding site being very similar to ALK's both sequentially and structurally ^[6]. Other than inhibiting cMET, critotinib is regarded as a highly successful drug as it is very specific to ALK's kinase domain ATP binding site ^[6].