Department of Dermatology, University of Pennsylvania, 242 CRB, 415 Curie Boulevard, Philadelphia, PA 19104-6142 USA.
Cell Death Differ. 1996 Oct;3(4):357-71.
Epidermis is a self-renewing, multilayered tissue composed primarily of keratinocytes. The epidermal keratinocyte follows a terminal differentiation pathway that under normal circumstances is tightly linked to its position within the epidermis and culminates in the formation of the protective barrier (stratum corneum) that constitutes the outermost layer of skin. Strong but pliant adhesive mechanisms are essential for normal functioning of the epidermis. In the epidermis, adhesion is mediated primarily by four structures: hemidesmosomes and focal adhesions, which function in cell-matrix adhesion, and desmosomes and adherens junctions, which function in cell-cell adhesion. In this review we concentrate on the transmembrane components of these structures, which are thought to mediate directly the adhesive function. Members of the integrin family of adhesion molecules comprise the transmembrane components of hemidesmosomes and focal adhesions, although hemidesmosomes also have a second, unrelated transmembrane molecule known as 'bullous pemphigoid antigen 2'. Members of the cadherin family are the transmembrane constituents of desmosomes and adherens junctions. Desmosomes consistently contain two types of cadherins (desmoglein and desmocollin), while adherens junctions may contain only one type of cadherin (E- or P-cadherin). Expression of most of the transmembrane components varies with the position of the keratinocyte within the epidermis and thus may reflect the degree of epidermal differentiation. All of the integrin subunits have been localized predominantly to the basal layer. In contrast, the cadherins show very complex expression patterns throughout the epidermis. Desmogleins and desmocollins (the desmosomal cadherins) are each encoded by three genes, and the expression of each gene is limited to certain epidermal layers. With respect to the cadherins of the adherens junction, it has been shown that E-cadherin is present throughout the epidermis, while P-cadherin is limited to the basal layer. Interestingly, these complex expression patterns of integrins and cadherins within the epidermis may not simply be passive events in differentiation; rather, evidence is accumulating that adhesion molecules can exert a dynamic role in epidermal differentiation/stratification. For example, decreased adhesion to extracellular matrix, induced by changes in one or more integrins, appears to be a signal that induces certain differentiation-related events. Even more profound effects on epidermal morphogenesis have been demonstrated for the cadherins. E- and/or P-cadherin is required not only to initiate normal intercellular junction formation but also for the subsequent development of a stratified epithelium. Thus, the findings to date with both integrins and cadherins suggest that adhesion molecules may function not just as direct mediators of adhesion, but also as regulators of epidermal stratification, differentiation, and morphogenesis.
表皮是一种自我更新的、多层组织，主要由角蛋白细胞组成。表皮角蛋白细胞遵循终末分化途径，在正常情况下与角蛋白细胞在表皮中的位置紧密相关，并最终形成构成皮肤最外层的保护屏障（角质层）。强有力但柔韧的粘附机制对于表皮的正常功能至关重要。在表皮中，粘附主要通过四种结构介导：半桥粒和粘着斑，它们在细胞-基质粘附中起作用，以及桥粒和粘着连接，它们在细胞-细胞粘附中起作用。在这篇综述中，我们集中讨论这些结构的跨膜成分，这些成分被认为直接介导粘附功能。整合素家族的粘附分子是半桥粒和粘着斑的跨膜成分，尽管半桥粒还具有第二种不相关的跨膜分子，称为“大疱性类天疱疮抗原 2”。钙粘蛋白家族的成员是桥粒和粘着连接的跨膜成分。桥粒始终包含两种类型的钙粘蛋白（桥粒芯糖蛋白和桥粒胶蛋白），而粘着连接可能只包含一种类型的钙粘蛋白（E-或 P-钙粘蛋白）。大多数跨膜成分的表达随角蛋白细胞在表皮中的位置而变化，因此可能反映了表皮分化的程度。所有整合素亚基都主要定位于基底层。相比之下，钙粘蛋白在整个表皮中表现出非常复杂的表达模式。桥粒芯糖蛋白和桥粒胶蛋白（桥粒钙粘蛋白）分别由三个基因编码，每个基因的表达仅限于某些表皮层。关于粘着连接的钙粘蛋白，已经表明 E-钙粘蛋白存在于整个表皮中，而 P-钙粘蛋白仅限于基底层。有趣的是，表皮中整合素和钙粘蛋白的这种复杂表达模式可能不仅仅是分化过程中的被动事件；相反，越来越多的证据表明，粘附分子可以在表皮分化/分层中发挥动态作用。例如，通过一个或多个整合素的变化诱导的细胞外基质粘附减少似乎是诱导某些分化相关事件的信号。钙粘蛋白对表皮形态发生的影响更为深远。E-和/或 P-钙粘蛋白不仅需要启动正常的细胞间连接形成，还需要随后的分层上皮发育。因此，迄今为止与整合素和钙粘蛋白有关的发现表明，粘附分子不仅可以作为直接的粘附介质，还可以作为表皮分层、分化和形态发生的调节剂。
