The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that was discovered as an oncogene in anaplastic large cell lymphomas, but also plays an oncogenic role in other cancer types, such as non-small-cell lung cancer (NSCLC), neuroblastoma and glioblastoma. The activation of anaplastic lymphoma kinase (ALK) requires the binding of the ligand pleiotrophin (PTN) or midkine (MDK), which induces the dimerization of the receptor. ALK dimers undergo trans-autophosphorylation, resulting in a fully activated receptor that triggers downstream signaling cascades such as RAS signaling, PI3K signaling and IRS1 signaling. In cancer, ALK gene frequently undergoes translocation, resulting in formation of fusion ALK proteins, such as NPM-ALK and EML4-ALK. These fusion proteins consist of the C-terminal region of ALK, with the kinase domain and the effector protein binding domain, while the N-terminus contains the dimerization domain of the ALK fusion partner. Fusion proteins of ALK are therefore capable of ligand-independent dimerization, resulting in constitutive ALK signaling. ALK can also undergo ligand-independent activation through RPTPB/RPTPZ.
ALK gene is mainly expressed in the developing central and peripheral nervous system. PTN and MDK have neuroprotective effect against neurotoxic agents and in neurodegenerative diseases.
For review, please refer to Chiarle et al. 2008, Wellstein 2012, Deuel 2013, Hallberg and Palmer 2013, Kadomatsu et al. 2013, Winkler and Yao 2014, Herradon and Perez-Garcia 2014, Janoueix-Lerosey et al. 2018, Della Corte et al, 2018.