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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.

La FSH est une des hormones clés qui régule la reproduction chez les mammifères. Chez le mâle, elle cible les cellules de Sertoli, qui expriment le RFSH. La cellule de Sertoli a un rôle trophique important pour le bon développement de la spermatogenèse. Dans cette thèse, nous avons établi le premier traductome, c’est-à-dire l’ensemble des ARNm en cours de traduction, dépendant du RFSH. La traduction de certains ARNm significativement modulés par la FSH exercerait un rétrocontrôle sur la signalisation FSH-dépendante. L’analyse du protéome nous a permis de valider ce traductome au niveau systémique. Nous avons également démontré l’implication des β-arrestines dans la traduction d’ARNm dépendante de la FSH. Les β-arrestines forment un assemblage moléculaire avec le module de traduction p70S6K/rpS6. Cet assemblage est impliqué dans la traduction des ARNm 5’TOP, qui encodent la machinerie traductionnelle. C’est l’activation FSHdépendante des protéines G qui promeut l’activation de p70S6K au sein du module β-arrestines/ p70S6K/ rpS6. Ce travail constitue une nouvelle avancée sur les mécanismes grâce auxquels la FSH exerce sa fonction biologique de dans ses cellules-cibles naturelles de la gonade mâle. / FSH is one of the key hormones that regulate the reproductive function in mammals. In the male, FSH targets Sertoli cells, which express the FSHR. Sertoli cells play an important trophic role in the development of spermatogenesis. Here, we have provided the first FSHR-induced translatome, that encompasses all the mRNA being actively translated. The translation of some mRNAs significantly modulated by FSH may exert a feedback control on FSH-dependent signaling. The analysis of the proteome has validated the FSHR translatome at the systems level. We also demonstrated the involvement of β-arrestins in the FSH-stimulated translation of mRNA. β-arrestins form a molecular assembly with the p70S6K / rpS6 translation module. This molecular assembly is involved in the translation of 5'TOP mRNA, which encode proteins of the translational machinery. FSH-activated G proteins leads to p70S6K activation within the β-arrestins/ p70S6K/ rpS6 module. This work provides new advance on the mechanisms whereby FSH exerts its biological function in its natural target cells of the male gonad.