Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling.
Neuropilin-1 (NRP1) is a co-receptor for vascular endothelial growth factor (VEGF) that enhances the angiogenic signals cooperatively with VEGFR2. VEGF signaling is essential for physiological and pathological angiogenesis through its effects on vascular endothelial cells (ECs) and smooth muscle cells (SMCs), but the mechanisms coordinating this response are not well understood. Here we show that a substantial fraction of NRP1 is proteoglycan modified with either heparan sulfate or chondroitin sulfate on a single conserved Ser. The composition of the NRP1 glycosaminoglycan (GAG) chains differs between ECs and SMCs. Glycosylation increased VEGF binding in both cell types, but the differential GAG composition of NRP1 mediates opposite responsiveness to VEGF in ECs and SMCs. Finally, NRP1 expression and its GAG modification post-transcriptionally regulate VEGFR2 protein expression. These findings indicate that GAG modification of NRP1 plays a critical role in modulating VEGF signaling, and may provide new insights into physiological and pathological angiogenesis.
Shintani
Yasunori
Y
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Takashima
Seiji
S
Asano
Yoshihiro
Y
Kato
Hisakazu
H
Liao
Yulin
Y
Yamazaki
Satoru
S
Tsukamoto
Osamu
O
Seguchi
Osamu
O
Yamamoto
Hiroyuki
H
Fukushima
Tomi
T
Sugahara
Kazuyuki
K
Kitakaze
Masafumi
M
Hori
Masatsugu
M
D000595:Amino Acid Sequence; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002809:Chondroitin Sulfates / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006025:Glycosaminoglycans / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D039942:Neuropilin-1 / Q000378:metabolism / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000502:physiology*
D002809:Chondroitin Sulfates; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D039942:Neuropilin-1; D012694:Serine; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2