c-Src and c-Yes are Two Unlikely Partners of Spermatogenesis and their Roles in Blood-Testis Barrier Dynamics

Abstract

Src family kinases (SFKs), in particular c-Src and c-Yes, are nonreceptor protein tyrosine kinases that mediate integrin signaling at focal adhesion complex at the cell-extracellular matrix interface to regulate cell adhesion, cell cycle progression, cell survival, proliferation and differentiation, most notably in cancer cells during tumorigenesis and metastasis. Interestingly, recent studies have shown that these two proto-oncogenes are integrated components of the stem cell niche and the cell-cell actin-based anchoring junction known as ectoplasmic specialization (ES) at the: (1) Sertoli cell-spermatid interface known as apical ES and (2) Sertoli-Sertoli cell interface known as basal ES which together with tight junctions (TJ), gap junctions and desmosomes constitute the blood-testis barrier (BTB). At the stem cell niche, these SFKs regulate spermatogonial stem cell (SSC) renewal to maintain the proper population of SSC/spermatogonia for spermatogenesis. At the apical ES and the BTB, c-Src and c-Yes confer cell adhesion either by maintaining the proper phosphorylation status of integral membrane proteins at the site which in turn regulates proteinprotein interactions between integral membrane proteins and their adaptors, or by facilitating androgen action on spermatogenesis via a nongenomic pathway which also modulates cell adhesion in the seminiferous epithelium. Herein, we critically evaluate recent findings in the field regarding the roles of these two unlikely partners of spermatogenesis. We also propose a hypothetical model on the mechanistic functions of c-Src and c-Yes in spermatogenesis so that functional experiments can be designed in future studies.

Differential effects of c-Src and c-Yes on the endocytic vesicle-mediated trafficking events at the Sertoli cell blood-testis barrier: an in vitro study

“…However, in these earlier reports, the downstream signaling molecules crucial to regulating endosomal sorting for the eventual recycling and/or degradation of endocytosed proteins remain unknown. Studies in c-Src and c-Yes, two members of the nonreceptor protein kinases, have illustrated their differential functions in cell physiology, in particular their roles in endocytic vesicular transport of proteins in other mammalian cells (34,39,49). For instance, c-Yes is monopalmitoylated, and it is transported from the Golgi pool of caveolin to plasma membrane to mediate endosome trafficking, illustrating its involvement in protein transcytosis; but c-Src is nonpalmitoylated, and it is shuffled between plasma membrane and late endosomes/lysosomes, suggesting that it may be intimately related to endosome-mediated degradation (11,34,39).…”

“…However, in these earlier studies, the underlying molecular mechanism(s) that affects targeting of the endocytic vesicles to the pathways of transcytosis and/or recycling vs. degradation remains unclear. Recently, multiple studies have shown that both of the closely related members of the Src family kinases, namely c-Src and c-Yes, are involved in endocytic vesicle-mediated trafficking of proteins in mammalian cells possibly via their regulations of the actin cytoskeleton (9,34), but the evidence was obscure as to how much they would perform overlapping functions in these events (49). We hypothesized that the Sertoli cell BTB utilized c-Yes and c-Src as the molecular "switches" in which c-Yes favors the targeting of the biotinylated and endocytosed BTB proteins for recycling vs. c-Src targeting the biotinylated and endocytosed proteins for intracellular degradation so that these two nonreceptor tyrosine kinases that work together provide a novel mechanism to regulate preleptotene spermatocyte transport across the BTB at stage VIII of the epithelial cycle.…”

Cardiotonic steroid ouabain stimulates expression of blood–testis barrier proteins claudin-1 and -11 and formation of tight junctions in Sertoli cells

“…Thus, interactions of CTS with sodium pumps trigger through the activation of the c-Src/c-Raf/Erk1/2/CREB signalling cascade the increased expression of the TJ proteins claudin-1 and claudin-11 and stimulate TJ formation. Activation of Src family kinases (SFK) like c-Src or c-Yes is critical for the formation and the dynamics of the BTB (Xiao et al, 2012). Whereas in other epithelia and also at the BTB c-Src regulates cell adhesion via its effects on endocytic vesicle-mediated protein trafficking, both c-Src and c-Yes confer cell adhesion at the apical ectoplasmic specialisation and at the BTB either by sustaining the phosphorylation status of integral membrane proteins and their peripheral adaptors (Xiao et al, 2011(Xiao et al, , 2012 or by promoting the non-classical signalling pathway of testosterone (Walker, 2010), which also modulates cell adhesion in the seminiferous epithelium (Xiao et al, 2012).…”

Stage-specific gene expression by Sertoli cells

“…Gene knockout studies indicate that in the neurons of the developing brain, MARCKS is required for the targeting of N-cadherin and of β-catenin to the proper location within the plasma membrane of these highly polarized cell [75]. It is therefore noteworthy that both β-catenin and N-cadherin are expressed by Sertoli cells and are essential to male fertility [67,76]. 294 Sertoli Cell Biology …”