Regulation of the Ras-MAPK and PI3K-mTOR Signalling Pathways by Alternative Splicing in Cancer

Table 1

Alternative splicing of Ras-MAPK and PI3K-mTOR signaling components.

Signalling component	Gene name	Splicing isoform activity	Type of cancer	Reference number
RTK	EGFR	Constitutively active receptor/soluble decoy isoform, enhanced signalling, survival, and tumorigenicity.	Glioblastoma, lung	[28, 47–49, 51, 56–58]
RTK	RON	Constitutively active receptor, enhanced signalling, invasion, and motility.	Glioblastoma, colon, breast, and gastric	[34, 35]
RTK	MET	Constitutively active receptor/soluble decoy isoform, enhanced/reduced signalling, invasion, and motility.	Ovarian, lung, and HCC	[38, 39]
RTK	FGFR	Induction of EMT, invasion, and motility.	Prostate, pancreatic, and breast	[28, 29, 36, 61]
RTK	INSR	Differential ligand binding (IGF-II) and oncogenic activity.	HCC, thyroid, and ovarian	[31, 37]
RTK	VEGFR	Soluble decoy isoform, enhanced/reduced angiogenesis, and survival.	Lung, breast	[28, 32]
Cytosolic kinase	Fyn	Enhanced/reduced kinase activity, survival of epithelial cells.	Unknown	[43]
Cytosolic kinase	mTOR	Constitutively active kinase, oncogenic activity.	HCC	[75]
Cytosolic kinase	S6K1	Tumor suppressor/oncogenic isoforms, activates/inhibits mTORC1.	Breast, lung	[14, 78]
Cytosolic kinase	A-Raf	Enhanced/reduced binding to Ras and activation of the MAPK pathway.	HCC, head, and neck	[45, 46]
Cytosolic kinase	B-Raf	Enhanced/reduced kinase activity, activation of the MAPK pathway, and resistance to BRAF kinase inhibitors.	Colon, melanoma	[20, 21, 40]
Cytosolic kinase	MEK1	Alternative pathway with a different substrate.	Unknown	[66, 67]
Cytosolic kinase	ERK1	Alternative pathway with different substrates.	Unknown	[66, 67]
Cytosolic kinase	MKNK2	Oncogenic isoform that enhances eIF4E phosphorylation and a tumor-suppressive isoform.	Lung, breast, colon, and pancreas	[14, 68]
Phospholipid phosphatase	PTEN	Active/inactive tumor suppressor.	Unknown	[71]
Phospholipid kinase	PI3K	Constitutively active kinase, enhanced downstream signalling.	Unknown	[69, 70]
Small GTPase	Ras	Enhanced/reduced binding to Raf and Rin and activation of the MAPK pathway.	Unknown	[32, 44]
GTPase activator (GAP)	TSC2	Inactivation of a tumor suppressor.	Tuberous sclerosis	[72–74]