Several studies have indicated that PLD regulated

Several studies have indicated that PLD-regulated PA signaling intersects with Rho-mediated cytoskeletal remodeling to drive mesenchymal-like cellular features, and it is known that Rho signaling has the potential to induce YAP/TAZ nuclear activity. Accordingly, Han et al. (2018) provide evidence that PA can impact YAP regulation downstream of Rho activation. However, they did not directly test whether stiffness-mediated cytoskeletal remodeling impacts PLD-PA-directed inhibition of LATS activity. This is relevant given that recent evidence from a study by Meng et al. (2018) suggests that inhibition of PDL1/2 in cells grown under condition of low stiffness results in the nuclear accumulation of YAP. This study proposes that at low stiffness, a collective increase in PIP2, PLD1 activity, and PA at the plasma membrane activates the RAP2 GTPase, which consequently inhibits nuclear YAP localization through upstream Hippo pathway signaling activation. This apparent contradictory finding that PA inhibits nuclear YAP localization can be reconciled by potential altered roles for PA in microenvironments of different stiffness. Meng et al. (2018) show that RAP2 is activated by low matrix stiffness and at endogenous levels promotes Hippo pathway signaling to restrict nuclear YAP accumulation. Therefore, PA function or localization may differ in response to mechanical signals or cytoskeletal alterations. In support of this idea, PA has been shown to distribute as a gradient under different polarizing conditions. In the case of the intestinal epithelium, PA accumulates at the apical domain of polarized intestinal epithelial cells and locally activates RAP2 via apical recruitment of the guanine nucleotide exchange factor PDZGEF (Gloerich et al., 2012). A similar gradient at the cell membrane may occur upon cortical INT-777 remodeling under low stiffness conditions. Meng et al. (2018) indeed argue that PA-mediated recruitment of PDZGEFs to the cell membrane activates RAP2 in low stiffness environments, leading to RAP2-induced activation of the Hippo pathway. Given that most experiments performed by Han et al. (2018) were under the stiff conditions of tissue culture plastic, a minimal PA gradient may have existed in their studies, which might alter PA localization or function to facilitate binding to LATS kinases and NF2 (see model in Figure 1). Stiff microenvironment conditions likely exist in YAP/TAZ-driven cancers, and therefore, the loss of PA gradient under those conditions may be relevant for driving PA-mediated LATS kinase inhibition. The mechanisms uncovered by Han et al. (2018) therefore advance our understanding of Hippo pathway signaling and like any important study raise interesting new questions and avenues for future research.
Introduction Spermatogenesis is critically dependent upon the proper functioning of the somatic cellular components in the testes. The somatic cells of the seminiferous epithelium- Sertoli cells (Sc) play an important role in regulating germ cell division and differentiation [1,2]. The post natal development of Sc involves two distinct phases- a proliferative state during the neonatal- infantile period when Sc remains immature and a functionally mature state that is attained at the onset of puberty when proliferation substantially ceases [2]. Sc proliferation during infancy is essential for creating a somatic mass which increases spermatogenic output during adulthood [3]. Functionally mature Sc are non proliferative and express genes which are essential for spermatogenic progression [2]. The functional maturation of Sc at the onset of puberty is crucial for robust germ cell differentiation at puberty. Defect in Sc proliferation and/or impaired functional maturation of Sc is detrimental to spermatogenesis and may be a possible cause of male infertility. The transition of Sc from a proliferative state to a functionally mature differentiated state is an important event that is regulated by both hormonal and non hormonal factors [2,4].