Ras Pathways on Prox1 and Lymphangiogenesis: Insights for Therapeutics

Abstract

Over the past couple of decades, lymphatics research has accelerated and gained a much-needed recognition in pathophysiology. As the lymphatic system plays heavy roles in interstitial fluid drainage, immune surveillance and lipid absorption, the ablation or excessive growth of this vasculature could be associated with many complications, from lymphedema to metastasis. Despite their growing importance in cancer, few anti-lymphangiogenic therapies exist today, as they have yet to pass phase 3 clinical trials and acquire FDA approval. As such, many studies are being done to better define the signaling pathways that govern lymphangiogenesis, in hopes of developing new therapeutic approaches to inhibit or stimulate this process. This review will cover our current understanding of the Ras signaling pathways and their interactions with Prox1, the master transcriptional switch involved in specifying lymphatic endothelial cell fate and lymphangiogenesis, in hopes of providing insights to lymphangiogenesis-based therapies.

Keywords: ERK pathway; PI3K-AKT pathway; Prox1; Ras; lymphangiogenesis; lymphatics.

Figure 1

Overview of ERK and AKT pathway on lymphangiogenesis. Both pathways influence different aspects of lymphatic remodeling upon activation of VEGFR-3, leading to downstream phosphorylation of signaling proteins (90). Crosstalk occurs across the pathways primarily as a means of negative regulation (–97). Current therapies to inhibit these signaling pathways involve the sequestration of VEGFR and its ligands (–100). Created with BioRender.com.

Figure 2

Prox1 protein domains and potential sites for modification. Data on sites across human, mouse, and rat Prox1 were pulled from PhosphoSitePlus (accessed October 1st, 2020). The following modification types and associated residues are: (1) Methylation (R392); (2) Sumoylation (K353, K556); (3) Acetylation (K707, K708); (4) Ubiquitylation (K212, K611, K700, K716); (5) Phosphorylation (S79, Y80, T91, T94, S142, S177, S179, S181, S197, S199, S291, S295, S372, S432, S472, S495, S511, S514, T518, S529, S530, S539, S545, S553, K557, K569, Y571, S574, T650). Created with BioRender.com.