Extracellular phosphorylation converts pigment epithelium–derived factor from a neurotrophic to an antiangiogenic factor

Abstract

The pigment epithelium-derived factor (PEDF) belongs to the superfamily of serine protease inhibitors (serpin). There have been 2 distinct functions attributed to this factor, which can act either as a neurotrophic or as an antiangiogenic factor. Besides its localization in the eye, PEDF was recently reported to be present also in human plasma. We found that PEDF purified from plasma is a phosphoprotein, which is extracellularly phosphorylated by protein kinase CK2 (CK2) and to a lesser degree, intracellularly, by protein kinase A (PKA). CK2 phosphorylates PEDF on 2 main residues, Ser24 and Ser114, and PKA phosphorylates PEDF on one residue only, Ser227. The physiologic relevance of these phosphorylations was determined using phosphorylation site mutants. We found that both CK2 and PKA phosphorylations of PEDF markedly affect its physiologic function. The fully CK2 phosphorylation site mutant S24, 114E abolished PEDF neurotrophic activity but enhanced its antiangiogenic activity, while the PKA phosphorylation site mutant S227E reduced PEDF antiangiogenic activity. This is a novel role of extracellular phosphorylation that is shown here to completely change the nature of PEDF from a neutrophic to an antiangiogenic factor. (Blood. 2005;105: 670-678)

Endostatin modulates VEGF-mediated barrier dysfunction in the retinal microvascular endothelium

“…(Maik-Rachline et al (2004)). Lysates were subsequently immunoprecipitated with rabbit anti-occludin antibody.…”

Protein Kinase CK2 and Angiogenesis

“…It was also shown that PDGF, the other growth factor implicated in angiogenesis, is phosphorylated by CK2. The CK2 phosphorylated form of PDGF has an elevated anti-angiogenic activity [48,49]. Recently, it turned out that PDG induced the CK2a' subunit expression [50].…”

Pigment epithelium-derived factor has a role in the progression of papillary thyroid carcinoma by affecting the HIF1α-VEGF signaling pathway

“…PEDF is one of the most promising anti-angiogenic factors; a number of studies have demonstrated its anti-angiogenic effects in various tumor models, including retinoblastoma, neuroblastoma, prostate cancer, melanoma, Wilms' tumor, pancreatic adenocarcinoma, hepatoblastoma, osteosarcoma, chondrosarcoma, human cervical carcinoma, gastric carcinoma, nasopharyngeal carcinoma, Lewis lung carcinoma, colorectal peritoneal carcinoma, glioma and breast cancer xenografts (20)(21)(22)(23)(24). The anti-angiogenic effect of PEDF is performed primarily through the disruption of microvascular network distribution (25)(26)(27)(28).…”