Fig. (3).

Schematic representation of the Ron receptor and of the downstream signalling pathways. (A) Ron is a single-pass, disulfide-linked α/β heterodimer. The α chain is an extracellular glycoprotein while the β chain is a transmembrane subunit that comprises an extra-cellular sequence, a short trans-membrane segment, a large cytoplasmic portion with intrinsic tyrosine kinase domain (TK) and a C-terminal tail. Residues and domains important for the Ron activity are indicated. In particular, the intracellular domain includes the tyrosine kinase catalytic site (white oval) flanked by distinctive juxtamembrane and carboxy-terminal sequences. Phosphorylation of two tyrosines within the kinase domain positively regulates the enzyme activity, whereas a serine residue in the juxtamembrane domain has a negative regulatory role. Two tyrosine residues in the carboxy-terminal region, when phosphorylated, form a specific docking site for multiple signal transducers and adaptors. Activation of Ron by MSP can initiate signaling through many pathways implicated in tumor progression and metastasis, such adhesion, invasion, mobility, proliferation and inhibition of apoptosis. (B) The constitutively active ΔRon isoform is generated through skipping of exon 11. This event is controlled by two adjacent splicing elements, a silencer and an enhancer, located in the central part and at the 3’ end of exon 12, respectively. These two regulatory elements may form a ‘‘control cassette’’ that tunes the strength of the acceptor site of intron 11 and thus the ratio between Ron and ΔRon transcripts. Splicing factor SF2/ASF directly binds to the enhancer and governs its activity. High levels of SF2/ASF increase the strength of the acceptor site of the intron 11, promote the production of ΔRon isoform and trigger morphological and molecular changes typical of the epithelial to mesenchymal transition (EMT). The primary function of the silencer could be to antagonize the enhancer and prevent exon skipping.