Epithelial cells are highly dependent during wound healing and tumorigenesis on the α6β4 integrin and its association with receptor tyrosine kinases. Prior work showed that phosphorylation of the β4 subunit upon matrix engagement depends on the matrix receptor syndecan-1 (Sdc1) engaging the cytoplasmic domain of the β4 integrin and coupling of the integrin to HER2. In this study, HER2-dependent haptotactic migration is compared to chemotactic migration stimulated by EGF. We find that whereas HER2-dependent migration depends on Sdc1, EGF-dependent migration depends on a complex consisting of EGFR, α6β4 and Sdc4. The two syndecans recognize distinct sites at the extreme C-terminus of the β4 integrin cytopl... More
Epithelial cells are highly dependent during wound healing and tumorigenesis on the α6β4 integrin and its association with receptor tyrosine kinases. Prior work showed that phosphorylation of the β4 subunit upon matrix engagement depends on the matrix receptor syndecan-1 (Sdc1) engaging the cytoplasmic domain of the β4 integrin and coupling of the integrin to HER2. In this study, HER2-dependent haptotactic migration is compared to chemotactic migration stimulated by EGF. We find that whereas HER2-dependent migration depends on Sdc1, EGF-dependent migration depends on a complex consisting of EGFR, α6β4 and Sdc4. The two syndecans recognize distinct sites at the extreme C-terminus of the β4 integrin cytoplasmic domain. The binding motif in Sdc1 is QEExYx, comprised in part by its syndecan-specific variable (V) region and in part by the second conserved (C2) region that it shares with other syndecans. A cell penetrating peptide containing this sequence competes for HER2-dependent epithelial migration and carcinoma survival, whereas it is without effect on the EGFR-stimulated mechanism. β4 mutants bearing mutations specific for Sdc1 and Sdc4 recognition act as dominant negative mutants to block cell spreading or cell migration that depends on HER2 or EGFR, respectively. The interaction of the α6β4 integrin with the syndecans appears critical for it to be utilized as a signaling platform; migration depends on α3β1 integrin binding to laminin 332, (LN332; also known as laminin 5), whereas antibodies that block α6β4 binding are without effect. These findings indicate that specific syndecan family members are likely to have key roles in α6β4 integrin activation by receptor tyrosine kinases.
