Extracellular phosphorylation converts pigment epithelium-derived factor from a neurotrophic to an antiangiogenic factor.
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.
Maik-Rachline
Galia
G
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Shaltiel
Shmuel
S
Seger
Rony
R
D047390:Casein Kinase II / Q000378:metabolism; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D005136:Eye Proteins / Q000097:blood* / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D016297:Mutagenesis, Site-Directed; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000097:blood* / Q000235:genetics; D010750:Phosphoproteins / Q000097:blood* / Q000235:genetics; D010766:Phosphorylation; D012175:Retinoblastoma; D015843:Serpins / Q000097:blood* / Q000235:genetics; D000099174:Pigment Epithelium-Derived Factor
D047390:Casein Kinase II; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D005136:Eye Proteins; D009414:Nerve Growth Factors; D010750:Phosphoproteins; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor