Fig. 1

Structure and regulation of E-cadherin gene and protein. Scheme represents human chromosome-16q22.1 cadherin cluster (CDH1/E-cadherin and CDH3/P-cadherin locus), and a regulation model both CDH1 locus and protein. CDH1 locus has 16 exons (black bars), cis-regulatory elements (DHSs, vertical arrows), transcription and translation start sites (small horizontal arrows), several enhancer sequences (green boxes and arrows) ─alternative intron 2-independent gene activation in late embryogenesis (alt), specific expression in (brain) or endoderm (enh), or ectoderm/tissues (tse1-4)─, downregulated sequences (red arrows) ─E-boxes and brain-specific silencer (sil)─, and yolk sac-specific elements outside of intron 2. Locus control region (LCR) could activate or downregulate gene activity (purple arrow). CpG methylation and E-box-bounded specific repressors (Snail1, slug, E47, δEF1/ZEB1 SIP1/ZEB2) control the promoter, as well as poly-ADP ribosylation and repressor inhibition (miR-200). MIR and MaLR regulatory-associated repetitive elements (light blue arrow) were bioinformatically found in introns 2 and 3, and are involved in exonization and increased novo intronic transcription. New transcripts have been revealed from intron 2-transcription and exon 11 skipping (red cross). In Drosophila melanogaster, CDH1-mRNA translation is suppressed by poly-ribosylation of HnRNP attached to E-cadherin 5’UTR. Human CDH1 pro-protein harbors topological domains: signal peptide (S), pro-peptide (PRO), extracellular with cadherin repeats EC1-EC5 domains, transmembrane (TM, with proximal CH2 and distal CH3), cytoplasmic domain (CD); binding sites of delta1-catenin and presenilin-1 (PS1), p120-ctn, β-catenin (βCTN), calcium; ubiquitination and short intracellular half-life sites rich in proline (P), glutamic acid (E), serine (S) and threonine (T) (PEST); motif highly conserved (Leu-Ser-Ser-Leu); acidic residues cluster of endocytic signal (DEE 602–604). Cleavage sites by proteases (scissors): metalloprotease (MMP), gamma-secretase/PS1 (presenilin-1) and caspase 3. Inhibitory or stimulatory phosphorylation sites for casein kinase-1 (CK1) (red) and CK2, GSK3β and PDK1 respectively. N-glycosylation at Asn-483 is essential for expression, folding and trafficking. Ligth blue horizontal lines indicate protein binding domains to E-cadherin.