Phosphorylation of threonine 1736 in the C-terminal tail of integrin β4 contributes to hemidesmosome disassembly

Abstract

T1736 is a novel phosphorylation site on the integrin β4 subunit that is phosphorylated downstream of protein kinase C and EGF receptor activation and is a substrate for protein kinase D1 in vitro and in cells. It contributes to the regulation of HD dynamics through modulating the association of β4 with plectin.

Epidermal Growth Factor (EGF) Regulates α5β1 Integrin Activation State in Human Cancer Cell Lines through the p90RSK-dependent Phosphorylation of Filamin A

“…Studies indicate that EGF can regulate integrin function by several mechanisms, including changing the amount of integrins on the cell surface, activating inside-out signaling pathways to affect ligand binding, and regulating outside-in signaling to selectively control integrin functions. In keratinocytes and squamous carcinoma, EGF signaling promotes ␣6␤4 integrin inactivation and hemidesmosome disassembly (23,24). In contrast, EGF positively regulates ␣5␤1 and ␣v␤5 integrin activation in ovarian and pancreatic cancer cells to promote invasion and metastasis (25,26).…”

Integrins in Wound Healing

“…7C). 106,107 Signaling through this receptor is required for normal re-epithelialization (Table 2). Recently, a 6 b 4 integrin was shown to complex with C4.4A (a structural homologue of uPAR), MMP-14, and disintegrin-metalloproteinase TACE to promote keratinocyte migration on laminin-332, possibly through focalized laminin-332 degradation.…”

The Calcium/Calcineurin Pathway Promotes Hemidesmosome Stability through Inhibition of β4 Integrin Phosphorylation

“…Most of the phosphorylation on the ␤4 integrin occurs on serine residues of the connecting segment domain (17). A cluster of serines at the beginning of the connecting segment, Ser 1356 -Ser 1360 -Ser 1364 , as well as at a nearby site, Ser 1424 (17)(18)(19)(20), or a threonine at the C-tail (21), have been shown to play an important role in HD stability. Mutation on some of these serine residues to alanine to impede phosphorylation reduces the disruptive activity of EGF on HD, increases the interaction of ␤4 and plectin, and can inhibit cell migration by stabilizing HD, indicating a function of ␤4 serine phosphorylation in HD regulation (17)(18)(19)(20).…”