Ets family members induce lymphangiogenesis through physical and functional interaction with Prox1.

Prox1 plays pivotal roles during embryonic lymphatic development and maintenance of adult lymphatic systems by modulating the expression of various lymphatic endothelial cell (LEC) markers, such as vascular endothelial growth factor receptor 3 (VEGFR3). However, the molecular mechanisms by which Prox1 transactivates its target genes remain largely unknown. Here, we identified Ets-2 as a candidate molecule that regulates the functions of Prox1. Whereas Ets-2 has been implicated in angiogenesis, its roles during lymphangiogenesis have not yet been elucidated. We found that endogenous Ets-2 interacts with Prox1 in LECs. Using an in vivo model of chronic aseptic peritonitis, we found that Ets-2 enhanced inflammatory lymphangiogenesis, whereas a dominant-negative mutant of Ets-1 suppressed it. Ets-2 also enhanced endothelial migration towards VEGF-C through induction of expression of VEGFR3 in collaboration with Prox1. Furthermore, we found that both Prox1 and Ets-2 bind to the VEGFR3 promoter in intact chromatin. These findings suggest that Ets family members function as transcriptional cofactors that enhance Prox1-induced lymphangiogenesis.

Yoshimatsu Y ，Yamazaki T ，Mihira H ，Itoh T ，Suehiro J ，Yuki K ，Harada K ，Morikawa M ，Iwata C ，Minami T ，Morishita Y ，Kodama T ，Miyazono K ，Watabe T ... -  《-》

Sumoylation of Prox1 controls its ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells.

Pan MR ，Chang TM ，Chang HC ，Su JL ，Wang HW ，Hung WC ... -  《-》

COUP-TFII regulates the functions of Prox1 in lymphatic endothelial cells through direct interaction.

Yamazaki T ，Yoshimatsu Y ，Morishita Y ，Miyazono K ，Watabe T ... -  《-》

Identification of targets of Prox1 during in vitro vascular differentiation from embryonic stem cells: functional roles of HoxD8 in lymphangiogenesis.

Harada K ，Yamazaki T ，Iwata C ，Yoshimatsu Y ，Sase H ，Mishima K ，Morishita Y ，Hirashima M ，Oike Y ，Suda T ，Miura N ，Watabe T ，Miyazono K ... -  《-》

Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1.

Flister MJ ，Wilber A ，Hall KL ，Iwata C ，Miyazono K ，Nisato RE ，Pepper MS ，Zawieja DC ，Ran S ... -  《-》