Introdução: Caderinas e integrinas são importantes para a manutenção da integridade tecidual e transdução de sinal durante o desenvolvimento da pele. A distribuição destas moléculas no desenvolvimento da pele humana foi investigada e associada com os marcadores de diferenciação, Citoqueratinas (CK) e involucrina (INV). Método: Usando a técnica de imunoistoquímica foram investigadas as proteínas E- e P- caderinas, integrinas beta- 1 e -4, CK 10, CK 14 e INV em fragmentos de pele de várias regiões corpóreas de 7 fetos humanos (semana gestacional de 4 a 24, todos pesando até 500 g). Resultados: Na fase inicial do desenvolvimento, integrinas beta-1 e -4 and E- and P- caderinas estavam presentes na membrana plasmática das células epiteliais em todos as camadas do epitélio. CK14 e CK10 foram observadas em todas as camadas epiteliais e a INV fracamente detectada em células da camada mais superficial. Em estágios mais avançados, integrinas foram detectadas em todas as camadas epiteliais, com expressão polarizada principalmente na camada basal. E- caderina foi detctada em todas as camadas, menos no estrato cornificado e a P- caderina foi observada em camadas mais profundas do epitélio. CK14 estava presente na camada basal, CK 10 no estrato suprabasal e a INV foi observada no estrato cornificado. Conclusão: Caderinas e integrinas são essenciais para o desenvolvimento da pele, sendo espacialmente e temporalmente regulados. Suas expressões são relatas com a expressão da maturação de marcadores da epiderme. / Introduction: Cadherins and integrins are important for maintenance of tissue integrity and in signal transduction during skin development. Distribution of these molecules in human skin development was investigated and associated with markers of differentiation, cytokeratins (CK) and involucrin (INV). Methods: Using immunohistochemistry expression of E- and P- cadherins, integrins beta-1 and -4, CK10, CK 14 and INV was assessed in skin fragments of 7 human fetuses (gestacional weeks ranged from 4 to 24, all weighing up to 500 g). Results: At initial phases of development, integrins beta-1 and -4 and E- and P- cadherins were present on epithelial cell membranes in all layers. CK 14 and CK 10 were expressed in all epithelial layers and INV weakly detected in the superficial layer. In more advanced stages, integrins were detected in all layers, but a marked polarized expression was seen in basal layer. E- cadherin was detected in all layers, but the cornified stratum and P- cadherin were observed in the lower layers. CK 14 was expressed in layer, CK 10 in suprabasal stratum and INV was observed in cornified layer. Conclusions: Cadherins and integrins are essential for skin development, being spatially and temporally regulated. Their expression is related with the expression of maturation markers of the epidermis.

Introdução: Caderinas e integrinas são importantes para a manutenção da integridade tecidual e transdução de sinal durante o desenvolvimento da pele. A distribuição destas moléculas no desenvolvimento da pele humana foi investigada e associada com os marcadores de diferenciação, Citoqueratinas (CK) e involucrina (INV). Método: Usando a técnica de imunoistoquímica foram investigadas as proteínas E- e P- caderinas, integrinas beta- 1 e -4, CK 10, CK 14 e INV em fragmentos de pele de várias regiões corpóreas de 7 fetos humanos (semana gestacional de 4 a 24, todos pesando até 500 g). Resultados: Na fase inicial do desenvolvimento, integrinas beta-1 e -4 and E- and P- caderinas estavam presentes na membrana plasmática das células epiteliais em todos as camadas do epitélio. CK14 e CK10 foram observadas em todas as camadas epiteliais e a INV fracamente detectada em células da camada mais superficial. Em estágios mais avançados, integrinas foram detectadas em todas as camadas epiteliais, com expressão polarizada principalmente na camada basal. E- caderina foi detctada em todas as camadas, menos no estrato cornificado e a P- caderina foi observada em camadas mais profundas do epitélio. CK14 estava presente na camada basal, CK 10 no estrato suprabasal e a INV foi observada no estrato cornificado. Conclusão: Caderinas e integrinas são essenciais para o desenvolvimento da pele, sendo espacialmente e temporalmente regulados. Suas expressões são relatas com a expressão da maturação de marcadores da epiderme. / Introduction: Cadherins and integrins are important for maintenance of tissue integrity and in signal transduction during skin development. Distribution of these molecules in human skin development was investigated and associated with markers of differentiation, cytokeratins (CK) and involucrin (INV). Methods: Using immunohistochemistry expression of E- and P- cadherins, integrins beta-1 and -4, CK10, CK 14 and INV was assessed in skin fragments of 7 human fetuses (gestacional weeks ranged from 4 to 24, all weighing up to 500 g). Results: At initial phases of development, integrins beta-1 and -4 and E- and P- cadherins were present on epithelial cell membranes in all layers. CK 14 and CK 10 were expressed in all epithelial layers and INV weakly detected in the superficial layer. In more advanced stages, integrins were detected in all layers, but a marked polarized expression was seen in basal layer. E- cadherin was detected in all layers, but the cornified stratum and P- cadherin were observed in the lower layers. CK 14 was expressed in layer, CK 10 in suprabasal stratum and INV was observed in cornified layer. Conclusions: Cadherins and integrins are essential for skin development, being spatially and temporally regulated. Their expression is related with the expression of maturation markers of the epidermis.

Despite the importance of integrins in epithelial cell biology surprisingly little is known about their regulation. It is known that they form hemidesmosomes (HDs), are actively involved in cell contacts during cell migration/invasion, and are key signaling molecules for survival and growth. However, there has been a distinct lack of understanding about what controls the dynamic integrin localization during cell activation and movement. Growth factors, such as EGF, are elevated during wound healing and carcinoma invasion leading to phosphorylation of ITGβ4 and the disassembly of the HD and mobilization of ITGβ4 to actin-rich protrusions. More recently the phosphorylation of a novel site on ITGβ4 (S1424) was found to be distinctly enriched on the trailing edge of migrating cells, suggesting a possible mechanism for the dissociation of ITGβ4 from HDs. Arrestin family member proteins are involved in the regulation of cell surface proteins and vesicular trafficking. In this study, we find that over-expression of arrestin family member ARRDC3 causes internalization and proteosome-dependent degradation of ITGβ4, while decreased levels of ARRDC3 stabilizes ITGβ4 levels. These results lead us to a new mechanism of ITGβ4 internalization, trafficking and degradation. During migration, ARRDC3 co-localizes with ITGβ4 on the lagging edge of cells but has a distinct distribution on the leading edge of cells. Additional immuno co-precipitation experiments demonstrate that ARRDC3 preferentially binds to ITGβ4 when phosphorylated on S1424. Using confocal microscopy, we show that the expression pattern of ARRDC3 on the lagging edge of a migrating cell is identical to the expression pattern of ITGβ4-pS1424. We demonstrate that ARRDC3 expression represses cell proliferation, migration, invasion, growth in soft agar and tumorigenicity. Collectively, our data reveals that ARRDC3 is a negative regulator of β4 integrin and demonstrates how this new pathway impacts biologic processes in stem cell and cancer biology. Additionally, as ARRDC3 is highly expressed in several tissues and conserved across species, our results are likely to be translated to other models.