Reactome | Active LTK binds IRS1

Active LTK binds IRS1

Stable Identifier

R-HSA-9842671

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane, cytosol

ReviewStatus

3/5

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MAPK phosphorylation is observed downstream of both activated full length LTK and activated chimeric receptors of LTK (Ueno et al, 1995; Ueno et al, 1996; Honda et al, 1999; Yamada et al, 2008; Farhan et al, 2010; Roll and Reuther, 2012).

Binding site studies with chimeric proteins identified two NPXY sites in LTK that appear to contribute to MAPK signaling, one at the C-terminus including the SHC-binding Y862 and one closer to the juxtamembrane region including Y485, that appears to recruit IRS1 (Ueno et al, 1995; Ueno et al, 1996). IRS1 is pulled down with stimulated chimeric LTK receptors and undergoes phosphorylation; these interactions are not observed with a Y485F chimeric receptor. IRS appears to contribute to the recruitment of GRB2 and SYP, and mutation of Y485 either singly or in combination with Y862 decreases the mitogenic activity, RAS signaling and phosphorylation of MAPK1 and MAPK3 (Ueno et al, 1995; Ueno et al, 1996). These protein interactions remain to be confirmed in the context of the full length LTK receptor.

Co-immunoprecipitation studies show that GRB2 and SOS1 are pulled down with SHC1 and the activated EGFR:LTK and CSF1R receptor chimeras (Ueno et al, 1995; Ueno et al, 1996). Mutation of the SHC binding site Y862 decreases signaling through the MAPK pathway, suggesting that the complex assembled by this site contributes to the phosphorylation of MAPK proteins and mitogenic signaling (Ueno et al, 1996).

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 Yazaki, Y, Mitani, K, Miyagawa, K, Kozutsumi, H, Hirai, H, Sasaki, K, Ueno, 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 Yazaki, Y, Hirano, N, Kozutsumi, H, Tanaka, T, Hirai, H, Sasaki, K, Ueno, H	J Biol Chem	1995
22347506	ALK-activating homologous mutations in LTK induce cellular transformation Reuther, GW, Roll, JD	PLoS One	2012
20548102	MAPK signaling to the early secretory pathway revealed by kinase/phosphatase functional screening Farhan, H, Hauri, HP, Sharan, R, Silberberg, Y, Mitrovic, S, Zerial, M, Wendeler, MW, Fava, E	J Cell Biol	2010
10445845	Heart-specific activation of LTK results in cardiac hypertrophy, cardiomyocyte degeneration and gene reprogramming in transgenic mice Yazaki, Y, Terasaki, F, Harada, K, Honda, H, Kawamura, K, Komuro, I, Hirai, H, Tanaka, Y, Ueno, H	Oncogene	1999
18849880	Expression of a chimeric CSF1R-LTK mediates ligand-dependent neurite outgrowth Nomura, T, Takano, K, Miyake, J, Fujita, S, Yamada, S, Miyake, M	Neuroreport	2008