Splice Variants of the RTK Family: Their Role in Tumour Progression and Response to Targeted Therapy

Abstract

Receptor tyrosine kinases (RTKs) belong to a family of transmembrane receptors that display tyrosine kinase activity and trigger the activation of downstream signalling pathways mainly involved in cell proliferation and survival. RTK amplification or somatic mutations leading to their constitutive activation and oncogenic properties have been reported in various tumour types. Numerous RTK-targeted therapies have been developed to counteract this hyperactivation. Alternative splicing of pre-mRNA has recently emerged as an important contributor to cancer development and tumour maintenance. Interestingly, RTKs are alternatively spliced. However, the biological functions of RTK splice variants, as well as the upstream signals that control their expression in tumours, remain to be understood. More importantly, it remains to be determined whether, and how, these splicing events may affect the response of tumour cells to RTK-targeted therapies, and inversely, whether these therapies may impact these splicing events. In this review, we will discuss the role of alternative splicing of RTKs in tumour progression and response to therapies, with a special focus on two major RTKs that control proliferation, survival, and angiogenesis, namely, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-1 (VEGFR1).

Keywords: EGFR; VEGFR; alternative splicing; angiogenesis; cancer; receptor tyrosine kinases; targeted therapies; tumourigenesis.

Figure 1

Schematic structure of the EGFR monomer. L: Ligand binding domain. CR: Cysteine-rich domain.

Figure 2

EGFR and its splicing variants. Alternative splicing of EGFR generates eight variants including those that encode soluble isoforms, sEGFRv2, sEGFRv3, and sEGFRv4, and those can encode non-soluble isoforms, mLEEK, EGFRvA, EGFRvIII, EGFRvIVa, and EGFRvIVb. For each splice variant, the number of exons (upper) and functional domains of the protein (lower) are represented. L: ligand binding, CR: Cysteine-Rich.

Figure 3

The different VEGFR1 splice variants, proteins and expression in tissues. (A) Schematic representation of full-length VEGFR1, sVEGFR1_i13, sVEGFR1_i14, sVEGFR1-e15a, and sVEGFR1-e15b mRNAs. Exons and introns are shown. TM: Transmembrane domain, KM1: ATP-binding domain, KM2: phosphotransferase domain; (B) Schematic representation of full-length VEGFR1 and sVEGFR1s proteins. Each splice variant isoform contains the first six extracellular Ig-like domains of VEGFR1, with (sVEGFR1-i14, sVEGFR1-e15a, sVEGFR1-e15b) or without (sVEGFR1-i13) a part of the last Ig-like domain, followed by a specific C-terminal end represented as a hatched box in the figure (adapted from [82]). aa represents the number of amino acids contained in the specific C-terminal part; (C) Percentage of expression of VEGFR1, sVEGFR1-i13, sVEGFR1-i14, and sVEGFR1-e15a mRNAs as indicated, according to the tissue type. sVEGFR1-e15b mRNA is undetectable in most of these tissues (adapted from [84]).