Table 1.

A list of ubiquitin E3 ligases and deubiquitination enzymes that have been found in regulation of associated genes in NSCLC

Genes	E3 Ligases	DUBs	Main function in lung cancer through the ubiquitin system	Ref
EGFR	c-Cbl, Cbl-b	USP8, USP2a, AMSH	EGFR is often overexpressed and mutated in lung cancer, especially in non-small cell lung cancer. Mono-ubiquitinated or poly-ubiquitinated EGFR upon EGF stimulation do not affect tyrosine kinase activity or signaling capacity but play a critical role in lysosomal targeting. Ubiquitination of EGFR can facilitate its endocytosis and degradation. Disruption of the negative regulatory system is associated with lung carcinogenesis, while deubiquitinating enzymes can reverse this modification and hence oppose endosomal sorting and lysosomal degradation in non-small cell lung cancers.	[45–48]
Ras	NEDD4–1, Rabex5, βTrCP1	–	RAS proteins are central mediators downstream of growth factor receptor signaling and therefore are critical for cell proliferation, survival, and differentiation. KRAS and NRAS mutations are more commonly found in lung cancers with adenocarcinoma histology. However, the ubiquitin system controls the subcellular localization and stability of Ras family protein in cancer cells, thereby contributing to the occurrences of tumor formation or metastasis.	[49–51]
Raf	RNF149, CHIP, TRAF2	–	Function as protein kinase to phosphorylate MAP 2 K1 directly, and thereby contributes to the MAPK signal transduction. Somatic mutations in BRAF, especially at valine 600 (V600), commonly occurred in non-small cell lung cancer, and this mutated BRAF can escape from degradation via the ubiquitin proteasome system. However, K63-linkaged poly-ubiquitination of BRAF impairs the activity in BRAF-mediated ERK activation, which induced by RNF149 E3 ligase. TRAF2 is a novel E3 ligase of BRAF K48-linkaged poly-ubiquitination which affects its stability.	[52–54]
PTEN	NEDD4–1, WWP2, XIAP, CHIP	USP7, USP13	It functions as a tumor suppressor that is mutated in a large number of cancers at high frequency and subcellular localization has been strongly implicated in the regulation of the PI3K/AKT pathway. Loss of PTEN expression is common in lung adenocarcinoma. Mono-ubiquitination and poly-ubiquitination of PTEN can be induced by NEDD4–1, WWP2, XIAP or CHIP, and deubiquitinated by USP7 or USP13 leading to its nuclear exclusion. Mono-ubiquitination of one of either Lys-13 or Lys-289 amino acid is sufficient to modulate PTEN compartmentalization. Phosphorylation of PTEN at Tyr-336 protects it from ubiquitin-mediated degradation probably by inhibiting its binding to NEDD4–1.	[55–58]
AKT	CHIP, BRCA1, NEDD4–1, Skp2, TRAF6, TRAF4	CYLD	The AKT kinase, which regulates many cell processes, plays a critical role in the development of multiple cancer types and tumorigenesis. In lung cancer, it is abnormally activated via the post-translational modification, including phosphorylation, ubiquitination and sumoylation, thereby impairing its subcellular location and cell signaling transduction. The ubiquitin system induces the ubiquitination of AKT with different lysine-linkage types either for the proteasome degradation or for the function alteration to affect the cell signaling transduction and control the evolution of cancer cells.	[59–61]
mTOR	Fbxw7, TRAF6	–	It functions as the main component of mTORC1 and mTORC2, and mTORC1 exerts a feedback control on upstream growth factor signaling including PI3K/AKT and MAPK signaling. Upon the stimuli of amino acid, the K63-likaged poly-ubiquitination of mTOR indirectly induced by TRAF6 promotes the mTORC1 activation to accelerate downstream signaling in non-small cell lung cancer. However, the K48-linkaged poly-ubiquitination of mTOR impacts both of mTORC1 and mTORC2 activities due to the proteasome degradation induced by Fbxw7.	[62–65]