In the canine MDCK cell line, CDH1 (E-cadherin) and CTNNB...

In the canine MDCK cell line, CDH1 (E-cadherin) and CTNNB1 (beta-catenin) are phosphorylated on tyrosine residues by recombinant SRC expressed from a construct obtained from the avian Rous sarcoma virus (Behrens et al. 1993; Fujita et al. 2002). Recombinant human CDH1 is phosphorylated by recombinant avian SRC at least on tyrosine residues Y753 and Y754, of which Y754 is critical for the subsequent CBLL1 (Hakai) binding (Mukherjee et al. 2012), which correspond to residues Y755 and Y756 in mouse CDH1, reported to be critical for CBLL1 binding in MDCK cell line (Fujita et al. 2002). Phosphorylation of Y755 and Y755 of a recombinant mouse CDH1 by a recombinant avian SRC in MDCK cells is necessary for ubiquitination, lysosomal targeting, and degradation of CDH1 (Palacios et al. 2005). Recombinant SRC and FYN kinases phosphorylate tyrosine residues of recombinant human CTNNB1 and JUP (plakoglobin), affecting their association with CDH1 and CTNNA1 (Miravet et al. 2003). While some of the tyrosine residues in the armadillo repeats of CTNNB1 and JUP are conserved, their phosphorylation pattern was inconsistent between SRC and FYN as well as between CTNNB1 and JUP for the same kinase (Miravet et al. 2003). Additional potential SRC and FYN target sites that are not conserved between CTNNB1 and JUP are also present (Miravet et al. 2003). Tyrosine phosphorylation at an unknown coordinate has been annotated for both CTNNB1 and JUP, until more data becomes available (Miravet et al. 2003). In human breast cancer cell line MCF7, tyrosine phosphorylation of CDH1 correlates with SRC activation downstream of calcium depletion-activated CDC42 RHO GTPase, and activated EGFR (Shen et al. 2008). In human hepatocellular carcinoma cell line HepG2, tyrosine phosphorylation of CDH1 and CTNND1 (p120 catenin or delta-catenin) correlates with and is dependent on the activation of SRC and FYN kinases, and negatively impacts CDH1 and CTNND1 binding (Chen et al. 2009). Activation of SRC in HepG2, followed by subsequent CBLL1-mediated ubiquitination of CDH1 and lysosomal degradation of CDH1, can be triggered by the integrin-interacting protein BSG (also known as Basigin or CD147) (Lu et al. 2018). In human colon carcinoma cell lines, RACK1 protein, which is able to bind to both SRC and CDH1, inhibits SRC-mediated tyrosine phosphorylation of CDH1, CTNNB1, and CTNND1, and the subsequent CBLL1-mediated ubiquitination of CDH1 (Swaminathan and Cartwright 2012). In the human colon carcinoma cell line T84, IFNG (interferon-gamma)-stimulated tyrosine phosphorylation of CDH1 and CTNND1 and the subsequent ubiquitination and removal of CDH1 from the plasma membrane, are dependent on FYN kinase (Smyth et al. 2012). FYN might also contribute to CDH1 downregulation indirectly, through upregulation of the CDH1 gene repressor SNAI1 (Snail) (Kim et al. 2011).

Phosphorylation of CTNND1 by SRC family kinases was studied in more detail using recombinant mouse CTNND1, where eight tyrosine residues, conserved in human CTNND1, were identified as phosphorylated by SRC (Mariner et al. 2001), although at least some of the sites can also be phosphorylated by tyrosine kinases unrelated to SRC (Mariner et al. 2004).

While the canonical PIP5K1C isoform of 668 amino acids promotes trafficking of CDH1 to the plasma membrane, the PIP5K1C splicing isoform of 707 amino acids was reported to promote lysosomal degradation of CDH1 in response to SRC kinase activation (Schill et al. 2014). PIP5K1C isoform of 707 amino acids is directly tyrosine phosphorylated by SRC on its C-terminus, which regulates its interaction with the endosomal sorting machinery and, in a RAB7-dependent manner, targets CDH1 to lysosomes for degradation (Schill et al. 2014).

SRC-mediated phosphorylation decreases the affinity of CTNNB1 and JUP for CDH1 (Miravet et al. 2003; Lu et al. 2018), and they are therefore shown to dissociate from CDH1 after SRC/FYN-mediated phosphorylation.