Wilhelmsen Kevin, Litjens Sandy H M, Kuikman Ingrid, Margadant Coert, van Rheenen Jacco, Sonnenberg Arnoud
Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Mol Biol Cell. 2007 Sep;18(9):3512-22. doi: 10.1091/mbc.e07-04-0306. Epub 2007 Jul 5.
Hemidesmosomes (HDs) are multiprotein adhesion complexes that promote attachment of epithelial cells to the basement membrane. The binding of alpha6beta4 to plectin plays a central role in their assembly. We have defined three regions on beta4 that together harbor all the serine and threonine phosphorylation sites and show that three serines (S1356, S1360, and S1364), previously implicated in HD regulation, prevent the interaction of beta4 with the plectin actin-binding domain when phosphorylated. We have also established that epidermal growth factor receptor activation, which is known to function upstream of HD disassembly, results in the phosphorylation of only one or more of these three residues and the partial disassembly of HDs in keratinocytes. Additionally, we show that S1360 and S1364 of beta4 are the only residues phosphorylated by PKC and PKA in cells, respectively. Taken together, our studies indicate that multiple kinases act in concert to breakdown the structural integrity of HDs in keratinocytes, which is primarily achieved through the phosphorylation of S1356, S1360, and S1364 on the beta4 subunit.
半桥粒（HDs）是促进上皮细胞与基底膜附着的多蛋白黏附复合物。α6β4与网蛋白的结合在其组装过程中起核心作用。我们在β4上定义了三个区域，这些区域共同包含所有丝氨酸和苏氨酸磷酸化位点，并表明先前与HD调节有关的三个丝氨酸（S1356、S1360和S1364）在磷酸化时会阻止β4与网蛋白肌动蛋白结合域的相互作用。我们还确定，已知在HD解体上游起作用的表皮生长因子受体激活会导致这三个残基中的一个或多个磷酸化，并使角质形成细胞中的HD部分解体。此外，我们表明β4的S1360和S1364分别是细胞中蛋白激酶C（PKC）和蛋白激酶A（PKA）磷酸化的唯一残基。综上所述，我们的研究表明，多种激酶协同作用破坏角质形成细胞中HD的结构完整性，这主要是通过β4亚基上的S1356、S1360和S1364磷酸化来实现的。
