Abstract
Three major laminin and collagen-binding integrins in skin (α6β4, α3β1, and α2β1) are involved in keratinocyte adhesion to the dermis and dissemination of skin cells during wound healing and/or tumorigenesis. Knockdown of α6 integrin in keratinocytes not only results in motility defects but also leads to decreased surface expression of the α2, α3, and β4 integrin subunits. Whereas α2 integrin mRNA levels are decreased in α6 integrin knockdown cells, α3 and β4 integrin mRNAs levels are unaffected. Expression of either α6 or α3 integrin in α6 integrin knockdown cells restores α2 integrin mRNA levels. Moreover, re-expression of α6 integrin increases β4 integrin protein at the cell surface, which results in an increase in α3 integrin expression via activation of initiation factor 4E-binding protein 1. Our data indicate that the α6β4 integrin is a master regulator of transcription and translation of other integrin subunits and underscore its pivotal role in wound healing and cancer.
Highlights
Keratinocyte migration involves the coordinated expression of various integrin heterodimers
Knockdown of ␣6 Integrin in Human Keratinocytes—In keratinocytes, ␣6 integrin preferentially pairs with 4 integrin to form ␣64 integrin, a receptor for laminin-332 [30]
The latter is in contrast to the localization of ␣64 integrin along the substratum-attached surface of control keratinocytes (Fig. 1C)
Summary
Keratinocyte migration involves the coordinated expression of various integrin heterodimers. Several other integrins enriched in the basal cells of the epidermis, including ␣31 integrin, a receptor for laminin-332, and ␣21 integrin, a receptor for collagen I, have been implicated in regulating wound healing of the skin and/or cell migration during tumorigenesis [15,16,17]. In the complete absence of ␣21 integrin, tumor metastasis is enhanced, most likely as a result of an inhibition of cancer cell adhesion to collagen [21] The latter result emphasizes that a precise regulation of expression of integrins in skin cells is a key regulator of migration in wound healing and metastasis, yet we know little about how such regulation is accomplished. The current data indicate that ␣64 integrin regulates the transcription of ␣2 integrin and the translation of ␣3 integrin
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