Shear stress-induced redistribution of vascular endothelial-protein-tyrosine phosphatase (VE-PTP) in endothelial cells and its role in cell elongation.
Vascular endothelial cells (ECs) are continuously exposed to shear stress (SS) generated by blood flow. Such stress plays a key role in regulation of various aspects of EC function including cell proliferation and motility as well as changes in cell morphology. Vascular endothelial-protein-tyrosine phosphatase (VE-PTP) is an R3-subtype PTP that possesses multiple fibronectin type III-like domains in its extracellular region and is expressed specifically in ECs. The role of VE-PTP in EC responses to SS has remained unknown, however. Here we show that VE-PTP is diffusely localized in ECs maintained under static culture conditions, whereas it undergoes rapid accumulation at the downstream edge of the cells relative to the direction of flow in response to SS. This redistribution of VE-PTP triggered by SS was found to require its extracellular and transmembrane regions and was promoted by integrin engagement of extracellular matrix ligands. Inhibition of actin polymerization or of Cdc42, Rab5, or Arf6 activities attenuated the SS-induced redistribution of VE-PTP. VE-PTP also underwent endocytosis in the static and SS conditions. SS induced the polarized distribution of internalized VE-PTP. Such an effect was promoted by integrin engagement of fibronectin but prevented by inhibition of Cdc42 activity or of actin polymerization. In addition, depletion of VE-PTP by RNA interference in human umbilical vein ECs blocked cell elongation in the direction of flow induced by SS. Our results suggest that the polarized redistribution of VE-PTP in response to SS plays an important role in the regulation of EC function by blood flow.
Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Kemala Isnainiasih
KI
Mantilidewi
Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Electronic address: ymurata@med.kobe-u.ac.jp.
Yoji
Y
Murata
Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan.
Munemasa
M
Mori
Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Chihiro
C
Otsubo
Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Takenori
T
Kotani
Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan.
Shinya
S
Kusakari
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, 3-39-22 Showa-Machi, Maebashi, Gunma 371-8514, Japan.
Hiroshi
H
Ohnishi
Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan. Electronic address: matozaki@med.kobe-u.ac.jp.
Takashi
T
Matozaki
D000199:Actins / Q000378:metabolism; D000818:Animals; D001775:Blood Circulation; D049108:Cell Enlargement; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000378:metabolism / Q000502:physiology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology / Q000502:physiology; D006801:Humans; D051379:Mice; D034622:RNA Interference; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics / Q000378:metabolism*; D033081:Shear Strength; D013314:Stress, Mechanical; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D020764:cdc42 GTP-Binding Protein
Endothelial Cell; Membrane Proteins; Protein-tyrosine Phosphatase (Tyrosine Phosphatase); Shear Stress; Small GTPases