Phosphorylation of a Novel Site on the β4 Integrin at the Trailing Edge of Migrating Cells Promotes Hemidesmosome Disassembly
Phosphorylation of a Novel Site on the β4 Integrin at the Trailing Edge of Migrating Cells Promotes Hemidesmosome Disassembly
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DOI：
10.1091/mbc.e08-06-0646
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发表时间：
2009-01-01
影响因子：
3.3
通讯作者：
Rabinovitz, Isaac
中科院分区：
文献类型：
--
作者：
Germain, Emily C.;Santos, Tanya M.;Rabinovitz, Isaac
半粒酶是一种多蛋白结构，可将上皮细胞固定在基底膜上。HD成分包括α 6 β 4整合素、粘附素和BPAGs（大疱性类天疱疮抗原）。角质形成细胞中的HD分解是细胞迁移的必要条件，EGF可通过β 4整合素磷酸化诱导HD分解。我们在β 4整合素上发现了一个新的磷酸化位点：S-1424。通过突变S -> A（1424）来防止磷酸化导致β 4进入hd的增加和对egf诱导的分解的抗性。相反，突变S -> D-1424（模拟磷酸化）部分动员hd中的β 4，并增强其他磷酸化位点的分解作用。与先前描述的在生长因子刺激下磷酸化的位点相反，S-1424已经表现出高度的构成磷酸化，这表明了其他功能。S-1424的组成性磷酸化在迁移角化细胞的后缘明显富集，在那里hd被分解。虽然发现大部分s -1424磷酸化的β - 4与HDs分离，但大量的β - 4与HDs靠近细胞边缘，与粘连蛋白共定位，但总是排除BPAGs，这表明phospho-S-1424可能是将β - 4与BPAGs分离的机制。S-1424磷酸化依赖于PKC。这些数据表明，S-1424在细胞收缩诱导的hd逐渐解体中起重要作用。
Hemidesmosomes (HDs) are multiprotein structures that anchor epithelial cells to the basement membrane. HD components include the alpha 6 beta 4 integrin, plectin, and BPAGs (bullous pemphigoid antigens). HD disassembly in keratinocytes is necessary for cells to migrate and can be induced by EGF through beta 4 integrin phosphorylation. We have identified a novel phosphorylation site on the beta 4 integrin: S-1424. Preventing phosphorylation by mutating S -> A(1424) results in increased incorporation of beta 4 into HDs and resistance to EGF-induced disassembly. In contrast, mutating S -> D-1424 (mimicking phosphorylation) partially mobilizes beta 4 from HDs and potentiates the disassembly effects of other phosphorylation sites. In contrast to previously described sites that are phosphorylated upon growth factor stimulation, S-1424 already exhibits high constitutive phosphorylation, suggesting additional functions. Constitutive phosphorylation of S-1424 is distinctively enriched at the trailing edge of migrating keratinocytes where HDs are disassembled. Although most of this S-1424-phosphorylated beta 4 is found dissociated from HDs, a substantial amount can be associated with HDs near the cell margins, colocalizing with plectin but always excluding BPAGs, suggesting that phospho-S-1424 might be a mechanism to dissociate beta 4 from BPAGs. S-1424 phosphorylation is PKC dependent. These data suggest an important role for S-1424 in the gradual disassembly of HDs induced by cell retraction.