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Abstract
During Xenopus gastrulation α5β1 integrin function is modulated in a temporally and spatially restricted manner, however, the regulatory mechanisms behind this regulation remain uncharacterized. Here we report that XGIPC/kermit2 binds to the cytoplasmic domain of the α5 subunit and regulates the activity of α5β1 integrin. The interaction of kermit2 with α5β1 is essential for fibronectin (FN) matrix assembly during the early stages of gastrulation. We further demonstrate that kermit2 regulates α5β1 integrin endocytosis downstream of activin signaling. Inhibition of kermit2 function impairs cell migration but not adhesion to FN substrates indicating that integrin recycling is essential for mesoderm cell migration. Furthermore, we find that the α5β1 integrin is colocalized with kermit2 and Rab 21 in embryonic and XTC cells. These data support a model where region specific mesoderm induction acts through kermit2 to regulate the temporally and spatially restricted changes in adhesive properties of the α5β1 integrin through receptor endocytosis.
Highlights
Cell adhesion is central to many biological processes including development, cancer metastasis, and wound healing
Chimeric integrin molecules consisting of the a4 extra-cellular domain and a variety of a subunit cytoplasmic domains reveal that while a number of a subunit cytoplasmic domains can substitute in cell adhesion, the a6 and a5 cytoplasmic domains are uniquely necessary for FN assembly [14]
It has previously been reported that GIPC binds to the Cterminal region of the cytoplasmic domain of the mammalian a5 and a6 integrin subunit [15,16]
Summary
Cell adhesion is central to many biological processes including development, cancer metastasis, and wound healing. Upon the initiation of gastrulation involuted mesoderm cells use a5b1 integrin to adhere and migrate directionally on this FN matrix [7,8,9]. As the expression of a5b1 integrin is ubiquitous in the Xenopus embryo, the differential use of a5b1 by ectoderm, endoderm and mesoderm suggests that this integrin exists in multiple activation states. Treatment of ectodermal cells with activin induces a mesodermal cell fate and results in cell spreading and migration on FN [10] using the RGD sequence in conjunction with the neighboring synergy site [5,11,12]. The spreading and migration of activin-treated ectodermal cells on FN occurs with same temporal regulation as observed in involuted mesoderm cells, indicating that in the embryo activation of the a5b1 integrin is under strict temporal and spatial regulation [6]. Chimeric integrin molecules consisting of the a4 extra-cellular domain and a variety of a subunit cytoplasmic domains reveal that while a number of a subunit cytoplasmic domains can substitute in cell adhesion, the a6 and a5 cytoplasmic domains are uniquely necessary for FN assembly [14]
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