Anaplastic Lymphoma Kinase (ALK) Receptor Tyrosine Kinase: A Catalytic Receptor with Many Faces

Abstract

The anaplastic lymphoma kinase (ALK) receptor is a membrane-bound tyrosine kinase. The pathogenesis of several cancers is closely related to aberrant forms of ALK or aberrant ALK expression, including ALK fusion proteins, ALK-activated point mutations, and ALK amplification. Clinical applications of different ALK inhibitors represent significant progress in targeted therapy. Knowledge of different aspects of ALK biology can provide significant information to further the understanding of this receptor tyrosine kinase. In this mini-review, we briefly summarize different features of ALK. We also summarize some recent research advances on ALK fusion proteins in cancers.

Keywords: ALK; ALK fusion proteins; ALK kinase inhibitors; aberrant forms; cancers; neuroblastoma; targeted therapy.

Figure 1

Domain structure of receptor tyrosine kinase families with anaplastic lymphoma kinase (ALK) highlighted. Modified from reference [5] with permission from Elsevier.

Figure 2

Summary of several ALK features. SP: Signal peptide; TM: Transmembrane domain; PTK: Protein kinase domain; G-rich: Glycine-rich domain; MAM: MAM domain; LDL: LDLα domain; ADD: Addiction/dependence domain.

Figure 3

Ribbon diagram of the human ALK catalytic domain structure with or without ALK inhibitors. (A) Crystal structures of the ALK catalytic domain (PDB ID: 3L9P). This structure contains glycerol molecules (gray small molecules). (B) Ribbon diagram depicting the crystal structure of the ALK catalytic domain in complex with crizotinib (PDB ID: 2XP2). (C) Ribbon diagram depicting the crystal structure of the ALK catalytic domain in complex with ceritinib (PDB ID: 4MKC). (D) Crystal structure of the ALK catalytic domain bound to brigatinib (PDB ID: 5J7H).

Figure 4

Schematic illustration of wild-type ALK, aberrant forms of ALK, ALK amplification, and ALK isoforms during signal transduction.