PI(4,5)P-dependent regulation of endothelial tip cell specification contributes to angiogenesis.

Dynamic positioning of endothelial tip and stalk cells, via the interplay between VEGFR2 and NOTCH signaling, is essential for angiogenesis. VEGFR2 activates PI3K, which phosphorylates PI(4,5)P to PI(3,4,5)P, activating AKT; however, PI3K/AKT does not direct tip cell specification. We report that PI(4,5)P hydrolysis by the phosphoinositide-5-phosphatase, INPP5K, contributes to angiogenesis.

Effective angiogenesis requires regulation of phosphoinositide signaling.

Phosphoinositide signaling regulates numerous downstream effectors that mediate cellular processes which influence cell cycle progression, migration, proliferation, growth, survival, metabolism and vesicular trafficking. A prominent role for phosphoinositide 3-kinase, which generates phosphatidylinositol 3,4,5-trisphosphate, a phospholipid that activates a plethora of effectors including AKT and FOXO during embryonic and postnatal angiogenesis, has been described. In addition, phosphatidylinositol 3-phosphate signaling is required for endosomal trafficking, which contributes to vascular remodeling.

Alternative splicing as a biomarker and potential target for drug discovery.

Alternative splicing is a key process of multi-exonic gene expression during pre-mRNA maturation. In this process, particular exons of a gene will be included within or excluded from the final matured mRNA, and the resulting transcripts generate diverse protein isoforms. Recent evidence demonstrates that approximately 95% of human genes with multiple exons undergo alternative splicing during pre-mRNA maturation.