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Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-2660826

PubChem

R-HSA-2660826

Description

NOTCH1 t(7;9)(NOTCH1:M1580_K2555) mutant is expressed in a small subset of T-cell acute lymphoblastic leukemia (T-ALL) patients. This mutant protein results from a translocation that joins a portion of intron 24 of the NOTCH1 gene to the promoter sequence of T-cell receptor beta (TCRB), leading to overexpression of a truncated NOTCH1 protein in T-cells and their precursors. The truncated NOTCH1 contains amino acids 1580 to 2555 of the wild-type NOTCH1, lacking almost the entire extracellular domain, including EGF and LIN12 repeats (Ellisen et al. 1991). As EGF repeats are needed for NOTCH1 interaction with its ligands (DLL1, DLL4, JAG1, JAG2), the mutant NOTCH1 t(7;9)(NOTCH1:M1580_K2555) does not bind a ligand. The constitutive activity of NOTCH1 t(7;9)(NOTCH1:M1580_K2555) is based on its constitutive proteolytic processing into NOTCH1 intracellular domain (NICD1) by ADAM10/17 protease and gamma-secretase complex, as proteolytic cleavage sites are exposed in the absence of ligand binding in the mutant protein. Constitutively produced NICD1 accumulates in the nucleus, leading to aberrant activation of NOTCH1 target genes which play important roles in the development of T lymphocytes (Washburn et al. 1997. Radtke et al. 1999, Maillard et al. 2004, Sambandam et al. 2005, Tan et al. 2005). Infection of bone marrow cells with recombinant retroviruses that code for truncated NOTCH1 that resembles t(7;9)(NOTCH1:M1580_K2555) resulted in T-ALL-like illness in a portion of mice that received the infected bone-marrow transplant, with all tumors overexpressing truncated forms of NOTCH1 (Pear et al. 1996).

Click on a node on the pathway to see its details. Glycoproteins are marked with a glycoprotein icon in their name.

SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

Displaying **all 7** entries
UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
O00548	Delta-like protein 1	DLL1 UNQ146/PRO172	view
O14672	Disintegrin and metalloproteinase domain-containing protein 10	ADAM10 KUZ MADM	view
P46531	Neurogenic locus notch homolog protein 1	NOTCH1 TAN1	view
P78504	Protein jagged-1	JAG1 JAGL1	view
P78536	Disintegrin and metalloproteinase domain-containing protein 17	ADAM17 ADAM18 CSVP TACE hCG_23065	view
Q9NR61	Delta-like protein 4	DLL4 UNQ1895/PRO4341	view
Q9Y219	Protein jagged-2	JAG2	view

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