Table 1.

Examples of pre-mRNA alternative splicing (AS) of various receptor tyrosine kinases and functional consequences.

RTK	Splicing Events	Functional Consequences	References
ALK	Skipping of exons 2–3 Skipping of exons 4–11	Truncated proteins with increased constitutive kinase activity and transformation potential in neuroblastoma	[8]
	Skipping of exon 23 or exon 27	Truncated proteins lacking the full kinase domain of ALK in Non Small Cell Lung Carcinoma	[9]
AXL	Skipping of exon 10	Shorter AXL protein with same transforming potential as full-length AXL	[10]
DDR	Exon skipping or inclusion	Distinct binding partners Differential activation by collagen	[11]
EGFR	Inclusion of exon 10, 9a, 16 or 17	Soluble receptors acting as negative regulators of EGFR signalling	[12]
	Skipping of exons 2–7	Constitutively active receptor	[13]
		Enhanced signalling, survival, and tumourigenicity	[14]
	Skipping of exons 2–22	Enhanced migration and invasion Cancer stem cells marker	[15]
ERB4	N- and C-terminal alternative splicing generating four isoforms	Modulation of sub-cellular localization and partner binding	[16]
FGFR	Mutually exclusive exon 8 or 9	Generation of distinct extracellular Ig-like domain III with distinct affinity for FGF ligands	[17]
		Induction of Epithelial to Mesenchymal Transition (EMT), invasion and motility	[18]
INSR	Skipping or inclusion of exon 11	Generation of INSR-A and INSR-B splice variants that respond differentially to IGF-II and insulin ligands and differentially activate the RAS/MAPK pathway	[19]
MET	Skipping of exon 14	Activation of MET kinase activity Oncogenic transformation	[20]
		Increased sensitivity to MET inhibitors	[21]
RET	3′-end alternative splicing generating multiple isoforms that differ in their C-terminal domain	Modulation of signalling partner binding Distinct sub-cellular localization and trafficking properties Transforming capacity	[22]
RON	Skipping of exon 11	Constitutively active receptor Enhanced signalling, invasion, motility	[23]
	Skipping of exons 15–19, 16–19, 16–17 and 16	Truncated protein lacking active kinase domain Dominant negative isoforms in lung cancers.	[24]
NTRK	Skipping of exons 6, 7 and 9	Constitutively active receptor Oncogenic function in neuroblastoma	[25]
VEGFR	Intron retention followed by premature polyadenylation	Soluble decoy receptor acting as negative regulator of VEGFR signalling	[26,27]
		Increased resistance to anti-angiogenic therapies	[28,29]

ALK: Anaplastic Lymphoma Kinase; DDR: Discoidin Domain Receptor; FGFR: Fibroblast Growth Factor Receptor; INSR: Insulin Receptor; RON: Receptor d’Origine Nantaise; NTRK: Neurotrophic Tyrosine Kinase Receptor.