Signaling by ALK

Many of the functional studies on ALK have been conducted in the context of oncogenic forms of the protein. In contrast, fewer studies have been conducted on the wild type protein under normal physiological conditions, and indeed, ALK was initially classed as an orphan receptor with no identified ligand. Two small heparin-binding growth factors, pleiotrophin (PTN) and midkine (MDK), were initially identified as potential ligands however subsequent studies failed to support this (Stoica et al, 2001; Stoica et al, 2002; Mathivet et al, 2007; Moog-Lutz et al, 2005; Motegi et al, 2004; reviewed in Wellstein et al, 2012; Winkler et al, 2014; Herradon and Perez-Garcia, 2014). More recently, ALKAL1 and ALKAL2 (also known as FAM150A and FAM150B) have been identified as ligands for both ALK and the related LTK receptor, albeit with differing potencies (Zhang et al, 2014; Guan et al, 2015; Reshetnyak et al, 2015; Reshetnyak et al, 2018; Fadeev et al, 2018; Reshetnyak et al, 2021; De Munck et al, 2021; Borenas et al, 2021; reviewed in Hallberg and Palmer, 2016). Whereas LTK receptor is potently activated by both ALKAL1 and ALKAL2, ALK is only weakly stimulated by ALKAL1. Ligand binding induces the dimerization of the receptor and transautophosphorylation, resulting in a fully activated receptor that triggers downstream signaling cascades such as RAS, PI3K and IRS1 signaling. ALK may also undergo ligand-independent activation through RPTPB/RPTPZ.

ALK is mainly expressed in the developing central and peripheral nervous system and plays a role in differentiation during development. In Drosophila and mice, ALK is a thinness gene involved in the resistance to weight gain. Through activation of STAT3 targets, ALK also appears to play a role in response to ethanol.