Identifier: R-HSA-9842663
Leukocyte tyrosine kinase (LTK) is a transmembrane receptor tyrosine kinase that is a member of the insulin growth factor receptor superfamily. LTK is most closely related to the ALK receptor, and may have originated as a result of a duplication event of the ALK gene (Krowelski and Dalla-Favera, 1991; Dornburg et al, 2021). The extracellular domains of ALK and LTK are characterized by a membrane proximal EGF-like (EGFL) module, a unique 250 amino acid glycine rich (GR) domain that, in Drosophila, is essential for function (Englund et al, 2003), as well as a TNF-like (TNFL) module. The ALK ECD additionally contains two MAM domains, an LDLa domain and a heparin-binding domain (HBD) that are not present in the LTK receptor (Iwahara et al, 1997; Morris et al, 1997; DeMunck et al, 2021). These differences in ECD may contribute to differences in the ligand binding affinities of the two receptors.
LTK is activated by the binding of cytokines ALKAL1 and ALKAL2 to the ECD (Zhang et al, 2014; Reshetnyak et al, 2015; Reshetnyak et al, 2018). Ligand binding induces trans-autophosphorylation in the intracellular domain of the receptor and promotes the interaction and activation of downstream signaling molecules such as SHC, IRS1, CBL and PI3K with the phosphorylated receptor (Kozutsumi et al, 1994; Honda et al, 1994; Ueno et al, 1995; Ueno et al, 1996; Ueno et al, 1997; Li et al, 2004; Yamada et al, 2008). Note however that much of the early functional studies on LTK were conducted before the identification of ALKAL1 and 2 as physiological ligands. In consequence, many of these studies were carried out using chimeric receptors consisting of the ECD (and stimulating ligands) of well-characterized receptors fused to the intracellular domain of LTK.
The exact role of LTK signaling is likewise not fully elucidated. Expression of the chimeric LTK proteins described above promotes neurite outgrowth and cell survival (Ueno et al, 1997; Yamada et al, 2008). A role for LTK in the regulation of transport from the ER to the Golgi has also been proposed, and one study suggests that LTK may actually bean ER-resident protein (Farhan et al, 2010; Centonze et al, 2019). More recently, fusions of LTK have been identified in non-small cell lung cancer (Izumi et al, 2021).