Reactome | Signaling by LTK

Signaling by LTK

Stable Identifier

R-HSA-9842663

Type

Pathway

Species

Homo sapiens

ReviewStatus

3/5

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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).

Literature References

PubMed ID	Title	Journal	Year
8910363	Growth and survival signals transmitted via two distinct NPXY motifs within leukocyte tyrosine kinase, an insulin receptor-related tyrosine kinase Ueno, H, Sasaki, K, Kozutsumi, H, Miyagawa, K, Mitani, K, Yazaki, Y, Hirai, H	J Biol Chem	1996
7650032	An epidermal growth factor receptor-leukocyte tyrosine kinase chimeric receptor generates ligand-dependent growth signals through the Ras signaling pathway Ueno, H, Hirano, N, Kozutsumi, H, Sasaki, K, Tanaka, T, Yazaki, Y, Hirai, H	J Biol Chem	1995
8084603	Human ltk receptor tyrosine kinase binds to PLC-gamma 1, PI3-K, GAP and Raf-1 in vivo Kozutsumi, H, Toyoshima, H, Hagiwara, K, Yazaki, Y, Hirai, H	Oncogene	1994
10445845	Heart-specific activation of LTK results in cardiac hypertrophy, cardiomyocyte degeneration and gene reprogramming in transgenic mice Honda, H, Harada, K, Komuro, I, Terasaki, F, Ueno, H, Tanaka, Y, Kawamura, K, Yazaki, Y, Hirai, H	Oncogene	1999
14695357	Gain-of-function polymorphism in mouse and human Ltk: implications for the pathogenesis of systemic lupus erythematosus Li, N, Nakamura, K, Jiang, Y, Tsurui, H, Matsuoka, S, Abe, M, Ohtsuji, M, Nishimura, H, Kato, K, Kawai, T, Atsumi, T, Koike, T, Shirai, T, Ueno, H, Hirose, S	Hum Mol Genet	2004
26630010	Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand-receptor interactions Reshetnyak, AV, Murray, PB, Shi, X, Mo, ES, Mohanty, J, Tome, F, Bai, H, Gunel, M, Lax, I, Schlessinger, J	Proc Natl Acad Sci U S A	2015
33196781	Comparative Genomics within and across Bilaterians Illuminates the Evolutionary History of ALK and LTK Proto-Oncogene Origination and Diversification Dornburg, A, Wang, Z, Wang, J, Mo, ES, López-Giráldez, F, Townsend, JP	Genome Biol Evol	2021
31227593	LTK is an ER-resident receptor tyrosine kinase that regulates secretion Centonze, FG, Reiterer, V, Nalbach, K, Saito, K, Pawlowski, K, Behrends, C, Farhan, H	J Cell Biol	2019
25331893	Deorphanization of the human leukocyte tyrosine kinase (LTK) receptor by a signaling screen of the extracellular proteome Zhang, H, Pao, LI, Zhou, A, Brace, AD, Halenbeck, R, Hsu, AW, Bray, TL, Hestir, K, Bosch, E, Lee, E, Wang, G, Liu, H, Wong, BR, Kavanaugh, WM, Williams, LT	Proc Natl Acad Sci U S A	2014
9174053	ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK) Morris, SW, Naeve, C, Mathew, P, James, PL, Kirstein, MN, Cui, X, Witte, DP	Oncogene	1997
14523447	Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion Englund, C, Lorén, CE, Grabbe, C, Varshney, GK, Deleuil, F, Hallberg, B, Palmer, RH	Nature	2003
18849880	Expression of a chimeric CSF1R-LTK mediates ligand-dependent neurite outgrowth Yamada, S, Nomura, T, Takano, K, Fujita, S, Miyake, M, Miyake, J	Neuroreport	2008
34819663	The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer Izumi, H, Matsumoto, S, Liu, J, Tanaka, K, Mori, S, Hayashi, K, Kumagai, S, Shibata, Y, Hayashida, T, Watanabe, K, Fukuhara, T, Ikeda, T, Yoh, K, Kato, T, Nishino, K, Nakamura, A, Nakachi, I, Kuyama, S, Furuya, N, Sakakibara-Konishi, J, Okamoto, I, Taima, K, Ebi, N, Daga, H, Yamasaki, A, Kodani, M, Udagawa, H, Kirita, K, Zenke, Y, Nosaki, K, Sugiyama, E, Sakai, T, Nakai, T, Ishii, G, Niho, S, Ohtsu, A, Kobayashi, SS, Goto, K	Nature	2021
9223670	The phosphatidylinositol 3' kinase pathway is required for the survival signal of leukocyte tyrosine kinase Ueno, H, Honda, H, Nakamoto, T, Yamagata, T, Sasaki, K, Miyagawa, K, Mitani, K, Yazaki, Y, Hirai, H	Oncogene	1997
30061385	Identification of a biologically active fragment of ALK and LTK-Ligand 2 (augmentor-α) Reshetnyak, AV, Mohanty, J, Tomé, F, Puleo, DE, Plotnikov, AN, Ahmed, M, Kaur, N, Poliakov, A, Cinnaiyan, AM, Lax, I, Schlessinger, J	Proc Natl Acad Sci U S A	2018
20548102	MAPK signaling to the early secretory pathway revealed by kinase/phosphatase functional screening Farhan, H, Wendeler, MW, Mitrovic, S, Fava, E, Silberberg, Y, Sharan, R, Zerial, M, Hauri, HP	J Cell Biol	2010
9053841	Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system Iwahara, T, Fujimoto, J, Wen, D, Cupples, R, Bucay, N, Arakawa, T, Mori, S, Ratzkin, B, Yamamoto, T	Oncogene	1997
1655406	The ltk gene encodes a novel receptor-type protein tyrosine kinase Krolewski, JJ, Dalla-Favera, R	EMBO J	1991
34646012	Structural basis of cytokine-mediated activation of ALK family receptors De Munck, S, Provost, M, Kurikawa, M, Omori, I, Mukohyama, J, Felix, J, Bloch, Y, Abdel-Wahab, O, Bazan, JF, Yoshimi, A, Savvides, SN	Nature	2021