Identification of ligand-induced proteolytic cleavage and ectodomain shedding of VEGFR-1/FLT1 in leukemic cancer cells.
Vascular endothelial growth factor receptor-1/fms-related tyrosine kinase 1 (VEGFR-1/FLT1) is expressed as a membrane-bound receptor tyrosine kinase and as an alternatively spliced soluble protein (sVEGFR-1) containing the 1-6 IgG-like domain of its ectodomain. sVEGFR-1 is known as a naturally occurring inhibitor of angiogenesis and as a surrogate marker for cancer progression; it is also linked to pregnancy-induced hypertension called preeclampsia and to avascularity of normal cornea. It remains an open question whether alternative mRNA splicing is the only mechanism by which sVEGFR-1 is generated. In this study, we show that in leukemic cancer cells, PlGF and VEGF-A both induce tyrosine phosphorylation of VEGFR-1 and render it susceptible to ectodomain shedding, resulting in the generation of sVEGFR-1 and an intracellular cytoplasmic fragment. Activation of protein kinase C and tumor necrosis factor-alpha-converting enzyme family metalloproteases are critically required for the occurrence of sVEGFR-1. Following the removal of the ectodomain, the remnant of VEGFR-1 remains attached to the membrane, and the activity of gamma-secretase/presenilin is required for its release from the cell membrane. We propose that sVEGFR-1 produced via ectodomain shedding plays a prominent role in the VEGF receptor system by antagonizing VEGF receptor signaling by acting as a dominant-negative form and/or forming a nonsignaling dimerizing complex with VEGF receptors.
Rahimi
Nader
N
Department of Pathology and Ophthalmology, Boston University Medical School, Boston, Massachusetts, USA. nrahimi@bu.edu
Golde
Todd E
TE
Meyer
Rosana D
RD
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D003593:Cytoplasm / Q000201:enzymology / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D008024:Ligands; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis*
D008024:Ligands; D040281:Vascular Endothelial Growth Factor Receptor-1; D011493:Protein Kinase C; D053829:Amyloid Precursor Protein Secretases