Neuropilin-1 promotes VEGFR-2 trafficking through Rab11 vesicles thereby specifying signal output

被引：159

作者：

Ballmer-Hofer, Kurt ^{[1
]}

Andersson, Anneli E. ^{[1
]}

Ratcliffe, Laura E. ^{[1
]}

Berger, Philipp ^{[1
]}

机构：

[1] Paul Scherrer Inst, CH-5232 Villigen, Switzerland

来源：

BLOOD | 2011年 / 118卷 / 03期

基金：

瑞士国家科学基金会;

关键词：

ENDOTHELIAL GROWTH-FACTOR; FACTOR RECEPTOR; KINASE-ACTIVITY; SEMAPHORIN-III; SPLICE VARIANT; PDZ-BINDING; CELLS; PROTEIN; TRANSDUCTION; ENDOSOMES;

D O I：

10.1182/blood-2011-01-328773

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development by activating 3 receptor tyrosine kinases (RTKs), VEGFR-1, -2, and -3, and by binding to coreceptors such as neuropilin-1 (NRP-1). We investigated how different VEGF-A isoforms, in particular VEGF-A(165)a and VEGF-A(165)b, control the balance between VEGFR-2 recycling, degradation, and signaling. Stimulation of cells with the NRP-1-binding VEGF-A(165)a led to sequential NRP-1-mediated VEGFR-2 recycling through Rab5, Rab4, and Rab11 vesicles. Recycling was accompanied by dephosphorylation of VEGFR-2 between Rab4 and Rab11 vesicles and quantitatively and qualitatively altered signal output. In cells stimulated with VEGF-A(165)b, an isoform unable to bind NRP-1, VEGFR-2 bypassed Rab11 vesicles and was routed to the degradative pathway specified by Rab7 vesicles. Deletion of the GIPC (synectin) binding motif of NRP-1 prevented transition of VEGFR-2 through Rab11 vesicles and attenuated signaling. Coreceptor engagement was specific for VEGFR-2 because EGFR recycled through Rab11 vesicles in the absence of known coreceptors. Our data establish a distinct role of NRP-1 in VEGFR-2 signaling and reveal a general mechanism for the function of coreceptors in modulating RTK signal output. (Blood. 2011;118(3):816-826)

引用

页码：816 / 826

页数：11

共 49 条

[1]

Adey NB, 2000, CANCER RES, V60, P35

[2] The ESCRT-III subunit hVps24 is required for degradation but not silencing of the epidermal growth factor receptor [J].

Bache, Kristi G. ;

Stuffers, Susanne ;

Malerod, Lene ;

Slagsvold, Thomas ;

Raiborg, Camilla ;

Lechardeur, Delphine ;

Walchli, Sebastien ;

Lukacs, Gergely L. ;

Brech, Andreas ;

Stenmark, Harald .

MOLECULAR BIOLOGY OF THE CELL, 2006, 17 (06) :2513-2523

[3]

Bates DO, 2002, CANCER RES, V62, P4123

[4] The CMT4B disease-causing proteins MTMR2 and MTMR13/SBF2 regulate AKT signalling [J].

Berger, Philipp ;

Tersar, Kristian ;

Ballmer-Hofer, Kurt ;

Suter, Ueli .

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 2011, 15 (02) :307-315

[5] Ligand-Stimulated VEGFR2 Signaling is Regulated by Co-Ordinated Trafficking and Proteolysis [J].

Bruns, Alexander F. ;

Herbert, Shane P. ;

Odell, Adam F. ;

Jopling, Helen M. ;

Hooper, Nigel M. ;

Zachary, Ian C. ;

Walker, John H. ;

Ponnambalam, Sreenivasan .

TRAFFIC, 2010, 11 (01) :161-174

[6] VEGF-A-stimulated signalling in endothelial cells via a dual receptor tyrosine kinase system is dependent on co-ordinated trafficking and proteolysis [J].

Bruns, Alexander F. ;

Bao, Leyuan ;

Walker, John H. ;

Ponnambalam, Sreenivasan .

BIOCHEMICAL SOCIETY TRANSACTIONS, 2009, 37 :1193-1197

[7] Rab7: A key to lysosome biogenesis [J].

Bucci, C ;

Thomsen, P ;

Nicoziani, P ;

McCarthy, J ;

van Deurs, B .

MOLECULAR BIOLOGY OF THE CELL, 2000, 11 (02) :467-480

[8]

Cai HB, 1999, J NEUROSCI, V19, P6519

[9] Vascular endothelial growth factor-induced endothelial cell proliferation is regulated by interaction between VEGFR-2, SH-PTP1 and eNOS [J].

Cai, J ;

Jiang, WG ;

Ahmed, A ;

Boulton, M .

MICROVASCULAR RESEARCH, 2006, 71 (01) :20-31

[10] Orf virus VEGF-E NZ2 promotes paracellular NRP-1/VEGFR-2 coreceptor assembly via the peptide RPPR [J].

Cebe-Suarez, Stephanie ;

Gruenewald, Felix S. ;

Jaussi, Rolf ;

Li, Xiujuan ;

Claesson-Welsh, Lena ;

Spillmann, Dorothe ;

Mercer, Andrew A. ;

Prota, Andrea E. ;

Ballmer-Hofer, Kurt .

FASEB JOURNAL, 2008, 22 (08) :3078-3086

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