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PMID: 22875452 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

An inside view: VEGF receptor trafficking and signaling.

Physiology (Bethesda, Md.) ·Vol. 27 ·No. 4 ·2012-08-00 ·Pages 213-22

Simons M

Abstract

Vascular endothelial growth factors (VEGF) and their receptors play a central role in the development of cardiovascular system and in vasculature-related processes in the adult organism. Given the critical role of this signaling cascade, intricate control systems have evolved to regulate its function. A new layer of added complexity has been the demonstration of the importance of endocytosis and intracellular trafficking of VEGF receptors in the regulation of VEGF signaling. In this review, we consider an evolving link between VEGF receptor endocytosis, trafficking, and signaling and their biological function.

MeSH Terms
Animals Endocytosis Protein Transport Receptors, Vascular Endothelial Growth Factor/metabolism Signal Transduction Vascular Endothelial Growth Factor A/metabolism
Chemicals
Vascular Endothelial Growth Factor A Receptors, Vascular Endothelial Growth Factor
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Simons Michael
Department of Internal Medicine, Section of Cardiovascular Medicine, Yale Cardiovascular Research Center, New Haven, Connecticut, USA. michael.simons@yale.edu
References (68)
68 references, click to expand
  1. A clathrin-dependent pathway leads to KRas signaling on late endosomes en route to lysosomes.
    J Cell Biol. 2009 Mar 23;184(6):863-79 PMID: 19289794
  2. TCR trafficking in resting and stimulated T cells.
    Crit Rev Immunol. 2004;24(1):67-86 PMID: 14995914
  3. Axl is essential for VEGF-A-dependent activation of PI3K/Akt.
    EMBO J. 2012 Apr 4;31(7):1692-703 PMID: 22327215
  4. VEGF signaling inside vascular endothelial cells and beyond.
    Curr Opin Cell Biol. 2012 Apr;24(2):188-93 PMID: 22366328
  5. Myosin VI is required for targeted membrane transport during cytokinesis.
    Mol Biol Cell. 2007 Dec;18(12):4750-61 PMID: 17881731
  6. Sequence-dependent sorting of recycling proteins by actin-stabilized endosomal microdomains.
    Cell. 2010 Nov 24;143(5):761-73 PMID: 21111236
  7. Neuropilin ligands in vascular and neuronal patterning.
    Biochem Soc Trans. 2009 Dec;37(Pt 6):1228-32 PMID: 19909252
  8. Targeting receptor kinases by a novel indolinone derivative in multiple myeloma: abrogation of stroma-derived interleukin-6 secretion and induction of apoptosis in cytogenetically defined subgroups.
    Blood. 2006 Mar 1;107(5):2079-89 PMID: 16278310
  9. Cloning and characterization of neuropilin-1-interacting protein: a PSD-95/Dlg/ZO-1 domain-containing protein that interacts with the cytoplasmic domain of neuropilin-1.
    J Neurosci. 1999 Aug 1;19(15):6519-27 PMID: 10414980
  10. Vascular endothelial growth factor and semaphorin induce neuropilin-1 endocytosis via separate pathways.
    Circ Res. 2008 Sep 12;103(6):e71-9 PMID: 18723443
  11. Rapid constitutive internalization and externalization of epidermal growth factor receptors in isolated rat hepatocytes. Monensin inhibits receptor externalization and reduces the capacity for continued endocytosis of epidermal growth factor.
    J Biol Chem. 1988 Sep 5;263(25):12199-203 PMID: 3261725
  12. Molecular mechanism and physiological functions of clathrin-mediated endocytosis.
    Nat Rev Mol Cell Biol. 2011 Jul 22;12(8):517-33 PMID: 21779028
  13. A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes.
    Cell. 2009 Mar 20;136(6):1110-21 PMID: 19303853
  14. GIPC participates in G protein signaling downstream of insulin-like growth factor 1 receptor.
    J Biol Chem. 2002 Feb 22;277(8):6719-25 PMID: 11751850
  15. Endocytic control of growth factor signalling: multivesicular bodies as signalling organelles.
    Nat Rev Mol Cell Biol. 2011 Nov 23;13(1):53-60 PMID: 22108513
  16. Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development.
    Sci Signal. 2010 Apr 06;3(116):ra26 PMID: 20371769
  17. Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments.
    J Cell Biol. 2006 Aug 14;174(4):593-604 PMID: 16893970
  18. Rac-dependent trans-endocytosis of ephrinBs regulates Eph-ephrin contact repulsion.
    Nat Cell Biol. 2003 Oct;5(10):879-88 PMID: 12973357
  19. Signal transduction by vascular endothelial growth factor receptors.
    Biochem J. 2011 Jul 15;437(2):169-83 PMID: 21711246
  20. The cytoplasmic domain of neuropilin 1 is dispensable for angiogenesis, but promotes the spatial separation of retinal arteries and veins.
    Development. 2011 Oct;138(19):4185-91 PMID: 21852397
  21. Endosomal targeting of MEK2 requires RAF, MEK kinase activity and clathrin-dependent endocytosis.
    Traffic. 2008 Sep;9(10):1776-90 PMID: 18657070
  22. Signalling ballet in space and time.
    Nat Rev Mol Cell Biol. 2010 Jun;11(6):414-26 PMID: 20495582
  23. Control of extracellular matrix assembly along tissue boundaries via Integrin and Eph/Ephrin signaling.
    Development. 2009 Sep;136(17):2913-21 PMID: 19641014
  24. The protein tyrosine phosphatase TCPTP controls VEGFR2 signalling.
    J Cell Sci. 2008 Nov 1;121(Pt 21):3570-80 PMID: 18840653
  25. Transcriptional profiling reveals a critical role for tyrosine phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial cell morphogenesis.
    FASEB J. 2009 May;23(5):1490-502 PMID: 19136612
  26. phospholipase C gamma-1 is required downstream of vascular endothelial growth factor during arterial development.
    Genes Dev. 2003 Jun 1;17(11):1346-51 PMID: 12782653
  27. GIPC is recruited by APPL to peripheral TrkA endosomes and regulates TrkA trafficking and signaling.
    Mol Cell Biol. 2006 Dec;26(23):8942-52 PMID: 17015470
  28. Novel role of ARF6 in vascular endothelial growth factor-induced signaling and angiogenesis.
    Circ Res. 2005 Mar 4;96(4):467-75 PMID: 15692085
  29. Kermit 2/XGIPC, an IGF1 receptor interacting protein, is required for IGF signaling in Xenopus eye development.
    Development. 2006 Sep;133(18):3651-60 PMID: 16914488
  30. Signal transduction and endocytosis: close encounters of many kinds.
    Nat Rev Mol Cell Biol. 2002 Aug;3(8):600-14 PMID: 12154371
  31. Synectin, syndecan-4 cytoplasmic domain binding PDZ protein, inhibits cell migration.
    J Cell Physiol. 2000 Sep;184(3):373-9 PMID: 10911369
  32. Endocytosis and signaling.
    Curr Opin Cell Biol. 2011 Aug;23(4):393-403 PMID: 21474295
  33. Ligand-stimulated VEGFR2 signaling is regulated by co-ordinated trafficking and proteolysis.
    Traffic. 2010 Jan;11(1):161-74 PMID: 19883397
  34. Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, beta-catenin, and the phosphatase DEP-1/CD148.
    J Cell Biol. 2003 May 26;161(4):793-804 PMID: 12771128
  35. Anchorage of VEGF to the extracellular matrix conveys differential signaling responses to endothelial cells.
    J Cell Biol. 2010 Feb 22;188(4):595-609 PMID: 20176926
  36. Role of synectin in lymphatic development in zebrafish and frogs.
    Blood. 2010 Oct 28;116(17):3356-66 PMID: 20631376
  37. Neuropilin-1 is required for endothelial tip cell guidance in the developing central nervous system.
    Dev Dyn. 2004 Nov;231(3):503-9 PMID: 15376331
  38. Molecular mechanisms and clinical applications of angiogenesis.
    Nature. 2011 May 19;473(7347):298-307 PMID: 21593862
  39. Selective regulation of arterial branching morphogenesis by synectin.
    Dev Cell. 2006 Jun;10(6):783-95 PMID: 16740480
  40. Syndecan 4 regulates FGFR1 signaling in endothelial cells by directing macropinocytosis.
    Sci Signal. 2012 May 08;5(223):ra36 PMID: 22569333
  41. APPL1 associates with TrkA and GIPC1 and is required for nerve growth factor-mediated signal transduction.
    Mol Cell Biol. 2006 Dec;26(23):8928-41 PMID: 17000777
  42. Syx, a RhoA guanine exchange factor, is essential for angiogenesis in Vivo.
    Circ Res. 2008 Sep 26;103(7):710-6 PMID: 18757825
  43. Molecular mechanism of multivesicular body biogenesis by ESCRT complexes.
    Nature. 2010 Apr 8;464(7290):864-9 PMID: 20305637
  44. A PDZ-binding motif as a critical determinant of Rho guanine exchange factor function and cell phenotype.
    Mol Biol Cell. 2006 Apr;17(4):1880-7 PMID: 16467373
  45. Rap1-PDZ-GEF1 interacts with a neurotrophin receptor at late endosomes, leading to sustained activation of Rap1 and ERK and neurite outgrowth.
    J Cell Biol. 2007 Aug 27;178(5):843-60 PMID: 17724123
  46. p14-MP1-MEK1 signaling regulates endosomal traffic and cellular proliferation during tissue homeostasis.
    J Cell Biol. 2006 Dec 18;175(6):861-8 PMID: 17178906
  47. Increasing traffic on vascular routes.
    Mol Aspects Med. 2011 Apr;32(2):112-22 PMID: 21536065
  48. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis.
    Nature. 2010 May 27;465(7297):487-91 PMID: 20445540
  49. VEGF regulates the mobilization of VEGFR2/KDR from an intracellular endothelial storage compartment.
    Blood. 2006 Oct 15;108(8):2624-31 PMID: 16638931
  50. GIPC and GAIP form a complex with TrkA: a putative link between G protein and receptor tyrosine kinase pathways.
    Mol Biol Cell. 2001 Mar;12(3):615-27 PMID: 11251075
  51. Identification of the switch in early-to-late endosome transition.
    Cell. 2010 Apr 30;141(3):497-508 PMID: 20434987
  52. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis.
    Nature. 2010 May 27;465(7297):483-6 PMID: 20445537
  53. Regulation of vascular endothelial growth factor receptor 2 trafficking and angiogenesis by Golgi localized t-SNARE syntaxin 6.
    Blood. 2011 Jan 27;117(4):1425-35 PMID: 21063020
  54. PDZ interaction sites in integrin alpha subunits. T14853, TIP/GIPC binds to a type I recognition sequence in alpha 6A/alpha 5 and a novel sequence in alpha 6B.
    J Biol Chem. 2001 Sep 28;276(39):36535-42 PMID: 11479315
  55. Endocytic regulation of TGF-beta signaling.
    Cell Res. 2009 Jan;19(1):58-70 PMID: 19050695
  56. Absence of erythrogenesis and vasculogenesis in Plcg1-deficient mice.
    J Biol Chem. 2002 Mar 15;277(11):9335-41 PMID: 11744703
  57. Neuropilin-1 promotes VEGFR-2 trafficking through Rab11 vesicles thereby specifying signal output.
    Blood. 2011 Jul 21;118(3):816-26 PMID: 21586748
  58. Endocytosis and signalling: intertwining molecular networks.
    Nat Rev Mol Cell Biol. 2009 Sep;10(9):609-22 PMID: 19696798
  59. GIPC, a PDZ domain containing protein, interacts specifically with the C terminus of RGS-GAIP.
    Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12340-5 PMID: 9770488
  60. VEGF receptor 2 endocytic trafficking regulates arterial morphogenesis.
    Dev Cell. 2010 May 18;18(5):713-24 PMID: 20434959
  61. VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding.
    J Cell Biochem. 2002;85(2):357-68 PMID: 11948691
  62. The endosomal protein Appl1 mediates Akt substrate specificity and cell survival in vertebrate development.
    Cell. 2008 May 2;133(3):486-97 PMID: 18455989
  63. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress.
    Nature. 2005 Sep 15;437(7057):426-31 PMID: 16163360
  64. Neuropilin-1/GIPC1 signaling regulates alpha5beta1 integrin traffic and function in endothelial cells.
    PLoS Biol. 2009 Jan 27;7(1):e25 PMID: 19175293
  65. Inhibition of vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis by the Kruppel-like factor KLF2.
    J Biol Chem. 2005 Aug 12;280(32):28848-51 PMID: 15980434
  66. Thrombospondin-1 inhibits VEGF receptor-2 signaling by disrupting its association with CD47.
    J Biol Chem. 2010 Dec 10;285(50):38923-32 PMID: 20923780
  67. Binding of internalized receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles.
    Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12735-40 PMID: 16908842
  68. Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development.
    Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15949-54 PMID: 15520367
Article Info
Journal
Physiology (Bethesda, Md.)
Abbr.
Physiology (Bethesda)
ISSN
1548-9221
DOI
10.1152/physiol.00016.2012
Email
michael.simons@yale.edu
Published
2012-08-00
Pages
213-22
Language
English
Region
United States
NLM ID
101208185
PMCID
PMC4037811
Subset
IM
Grants
NHLBI NIH HHS · HL-84619 · United States
NHLBI NIH HHS · P01 HL107205 · United States
NHLBI NIH HHS · R01 HL053793 · United States
NHLBI NIH HHS · R01 HL084619 · United States
NHLBI NIH HHS · HL-53793 · United States
External Links
PubMed source DOI: 10.1152/physiol.00016.2012 PMC Full Text View journal details
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