title: Venous malformation-causative TIE2 mutations mediate an AKT-dependent decrease in PDGFB.
abstract: Mutations in the endothelial cell (EC) tyrosine kinase receptor TIE2 cause inherited and sporadic forms of venous malformation. The recurrent somatic mutation L914F and common germline mutation R849W differ in terms of phosphorylation level, as well as sub-cellular localization and trafficking of the receptor. Previous studies have shed light on certain pathogenic properties of R849W, but the mechanisms of action of L914F are unknown. We used global gene expression profiling to study the effects of L914F on ECs. We found that L914F strongly dysregulates genes involved in vascular development, cell migration and extracellular matrix processing, while R849W has weak effects. We also demonstrate, for the first time, that TIE2-mutant ECs are deficient in the production of PDGFB, both in vitro and ex vivo in patient tissues. This defect is mediated by the chronic, ligand-independent activation of AKT by the mutant receptors. Inadequate secretion of the major mural cell attractant likely plays an important role in the development of abnormal vascular channels, contributing to the characteristic paucity of surrounding vascular smooth muscle cells.
authors: Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, 1200 Brussels, Belgium.
authors: Melanie
authors: M
authors: Uebelhoer
authors: Marjut
authors: M
authors: Nätynki
authors: Jaakko
authors: J
authors: Kangas
authors: Antonella
authors: A
authors: Mendola
authors: Ha-Long
authors: HL
authors: Nguyen
authors: Julie
authors: J
authors: Soblet
authors: Catherine
authors: C
authors: Godfraind
authors: Laurence M
authors: LM
authors: Boon
authors: Lauri
authors: L
authors: Eklund
authors: Nisha
authors: N
authors: Limaye
authors: Miikka
authors: M
authors: Vikkula
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D018095:Germ-Line Mutation; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D054079:Vascular Malformations / Q000235:genetics* / Q000378:metabolism*
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D020574:Proto-Oncogene Proteins c-sis; C498964:SLC16A10 protein, human; D042787:Receptor, TIE-2; D051057:Proto-Oncogene Proteins c-akt
references: J Biochem. 2008 Feb;143(2):199-206
references: 18006519
references: J Mol Med (Berl). 2005 Jan;83(1):58-63
references: 15526080
references: Eur J Hum Genet. 2010 Apr;18(4):414-20
references: 19888299
references: J Cell Biochem. 2006 Dec 15;99(6):1553-63
references: 16817200
references: Protein Cell. 2010 Jan;1(1):33-47
references: 21203996
references: J Cell Biol. 2001 Apr 30;153(3):543-53
references: 11331305
references: Hum Mol Genet. 1999 Jul;8(7):1279-89
references: 10369874
references: Science. 1997 Jul 11;277(5323):242-5
references: 9211853
references: Cell. 1996 Dec 27;87(7):1181-90
references: 8980225
references: Nat Cell Biol. 2008 May;10(5):527-37
references: 18425119
references: J Cell Biochem. 2011 Jan;112(1):289-98
references: 21069732
references: Angiogenesis. 2013 Jan;16(1):207-22
references: 23086340
references: Nat Cell Biol. 2008 May;10(5):513-26
references: 18425120
references: Am J Hum Genet. 2002 Apr;70(4):866-74
references: 11845407
references: Surg Today. 2006;36(3):283-6
references: 16493543
references: Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11400-6
references: 8876147
references: Angiogenesis. 2002;5(3):153-65
references: 12831056
references: J Invest Dermatol. 2008 Sep;128(9):2325-33
references: 18401423
references: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2975-80
references: 14978268
references: Science. 1997 Jul 4;277(5322):55-60
references: 9204896
references: Circ Res. 2000 Jan 7-21;86(1):24-9
references: 10625301
references: Nat Rev Cancer. 2008 Dec;8(12):942-56
references: 19029957
references: Cardiovasc Res. 2007 Dec 1;76(3):390-9
references: 17850776
references: Biochem J. 2005 Feb 15;386(Pt 1):15-27
references: 15554875
references: Matrix Biol. 2003 Mar;22(1):63-71
references: 12714043
references: Br J Dermatol. 2010 Feb 1;162(2):350-6
references: 19769632
references: Nucleic Acids Res. 2010 Jun;38(11):e120
references: 20215436
references: Development. 1999 Jun;126(14):3047-55
references: 10375497
references: J Clin Invest. 2005 Sep;115(9):2382-92
references: 16100571
references: Nat Genet. 2009 Jan;41(1):118-24
references: 19079259
references: Genes Dev. 2004 May 1;18(9):1060-71
references: 15132996
references: Biochem Biophys Res Commun. 2003 Aug 15;308(1):101-5
references: 12890486
references: J Biol Chem. 2000 Mar 31;275(13):9102-5
references: 10734041
references: Mol Syndromol. 2013 Apr;4(4):179-83
references: 23801934
references: Oncogene. 1999 Jan 7;18(1):1-8
references: 9926914
references: Genes Dev. 1994 Aug 15;8(16):1888-96
references: 7958864