title: Endoglin-mediated suppression of prostate cancer invasion is regulated by activin and bone morphogenetic protein type II receptors.
abstract: Mortality from prostate cancer (PCa) is due to the formation of metastatic disease. Understanding how that process is regulated is therefore critical. We previously demonstrated that endoglin, a type III transforming growth factor β (TGFβ) superfamily receptor, suppresses human PCa cell invasion and metastasis. Endoglin-mediated suppression of invasion was also shown by us to be dependent upon the type I TGFβ receptor, activin receptor-like kinase 2 (ALK2), and the downstream effector, Smad1. In this study we demonstrate for the first time that two type II TGFβ receptors are required for endoglin-mediated suppression of invasion: activin A receptor type IIA (ActRIIA) and bone morphogenetic protein receptor type II (BMPRII). Downstream signaling through these receptors is predominantly mediated by Smad1. ActRIIA stimulates Smad1 activation in a kinase-dependent manner, and this is required for suppression of invasion. In contrast BMPRII regulates Smad1 in a biphasic manner, promoting Smad1 signaling through its kinase domain but suppressing it through its cytoplasmic tail. BMPRII's Smad1-regulatory effects are dependent upon its expression level. Further, its ability to suppress invasion is independent of either kinase function or tail domain. We demonstrate that ActRIIA and BMPRII physically interact, and that each also interacts with endoglin. The current findings demonstrate that both BMPRII and ActRIIA are necessary for endoglin-mediated suppression of human PCa cell invasion, that they have differential effects on Smad1 signaling, that they make separate contributions to regulation of invasion, and that they functionally and physically interact.
authors: Department of Medicine, Northwestern University, Chicago, Illinois, USA.
authors: Michael J
authors: MJ
authors: Breen
authors: Diarmuid M
authors: DM
authors: Moran
authors: Wenzhe
authors: W
authors: Liu
authors: Xiaoke
authors: X
authors: Huang
authors: Calvin P H
authors: CP
authors: Vary
authors: Raymond C
authors: RC
authors: Bergan
mesh_terms: D030301:Activin Receptors, Type II / Q000737:chemistry / Q000378:metabolism; D028341:Activins / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D000071063:Endoglin; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D051898:Smad1 Protein; D028341:Activins; D030301:Activin Receptors, Type II; D052006:Bone Morphogenetic Protein Receptors, Type II; C425585:activin receptor type II-A
references: J Cell Biol. 1996 Jun;133(5):1109-21
references: 8655583
references: Coll Antropol. 2010 Apr;34 Suppl 2:119-25
references: 21302710
references: PLoS One. 2009 Dec 08;4(12):e8198
references: 20011660
references: Nat Genet. 1994 Dec;8(4):345-51
references: 7894484
references: EMBO J. 2009 Jun 3;28(11):1537-50
references: 19424179
references: Carcinogenesis. 2010 Dec;31(12):2145-54
references: 20884686
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Cardiovasc Res. 2005 Feb 15;65(3):599-608
references: 15664386
references: Clin Exp Metastasis. 2011 Jan;28(1):39-53
references: 20981476
references: J Cell Biol. 2003 Sep 15;162(6):1089-98
references: 12963706
references: Am J Physiol Lung Cell Mol Physiol. 2008 Nov;295(5):L744-55
references: 18723761
references: Carcinogenesis. 2010 Mar;31(3):359-66
references: 19736306
references: Prostate Cancer Prostatic Dis. 2004;7(2):105-10
references: 15175661
references: Cell. 1992 Jan 10;68(1):97-108
references: 1310075
references: Circ Res. 2004 Apr 30;94(8):1109-14
references: 15031260
references: Mol Cell Biol. 2007 Aug;27(16):5776-89
references: 17576816
references: Biochim Biophys Acta. 2009 Oct;1792(10):954-73
references: 19607914
references: J Pathol. 2008 Feb;214(3):394-404
references: 18072288
references: J Biol Chem. 1998 Dec 4;273(49):33011-9
references: 9830054
references: Am J Physiol Lung Cell Mol Physiol. 2004 Dec;287(6):L1241-7
references: 15286002
references: Cytokine Growth Factor Rev. 1998 Mar;9(1):49-61
references: 9720756
references: Nat Rev Cancer. 2003 Jun;3(6):453-8
references: 12778135
references: Cell Signal. 2007 Aug;19(8):1722-32
references: 17478078
references: Mol Biol Cell. 2002 Sep;13(9):3055-63
references: 12221115
references: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2814-9
references: 21576484
references: J Biol Chem. 2008 Feb 15;283(7):3877-88
references: 18042551
references: Cancer Res. 2008 Mar 15;68(6):2024-32
references: 18339885
references: Hum Mol Genet. 2003 Dec 15;12(24):3277-86
references: 14583445
references: EMBO J. 2012 Oct 3;31(19):3885-900
references: 22940691
references: Nat Genet. 2000 Sep;26(1):81-4
references: 10973254
references: Oncogene. 2003 Jul 31;22(31):4841-50
references: 12894225
references: Bone. 2006 Feb;38(2):154-66
references: 16126463
references: Am J Hum Genet. 2000 Sep;67(3):737-44
references: 10903931
references: J Cell Physiol. 2005 Aug;204(2):574-84
references: 15702480
references: Mol Cancer Res. 2008 Oct;6(10):1594-606
references: 18922975
references: J Urol. 2009 Jun;181(6):2749-59
references: 19375725
references: Cancer Metastasis Rev. 2010 Sep;29(3):465-82
references: 20730632
references: EMBO J. 2002 Apr 2;21(7):1743-53
references: 11927558
references: Blood. 2007 Mar 1;109(5):1953-61
references: 17068149
references: J Cell Biol. 2005 Aug 29;170(5):825-36
references: 16115956
references: Oncogene. 2002 Nov 28;21(54):8272-81
references: 12447690
references: Am J Pathol. 2007 Sep;171(3):1047-57
references: 17724140
references: J Biol Chem. 2004 Jul 30;279(31):32858-68
references: 15148318
references: Cell. 2008 Jul 25;134(2):215-30
references: 18662538
references: J Cell Biol. 2011 Jun 27;193(7):1305-19
references: 21708981
references: Oncogene. 2008 Oct 23;27(49):6322-33
references: 18663362
references: Cancer Res. 2005 Jul 1;65(13):5769-77
references: 15994952
references: Oncogene. 2004 Oct 7;23(46):7651-9
references: 15354178
references: J Biol Chem. 2007 May 11;282(19):13934-43
references: 17376778
references: Cytokine Growth Factor Rev. 2009 Oct-Dec;20(5-6):343-55
references: 19897402
references: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references: 20610543
references: Oncogene. 2007 Nov 8;26(51):7240-50
references: 17496924
references: J Biol Chem. 2002 Feb 15;277(7):4883-91
references: 11729207
references: Hum Mol Genet. 2002 Jun 15;11(13):1517-25
references: 12045205
references: J Biol Chem. 2005 Jul 1;280(26):24443-50
references: 15883158
references: J Biol Chem. 1992 Sep 25;267(27):19027-30
references: 1326540
references: ScientificWorldJournal. 2010 Dec 14;10:2367-84
references: 21170488
references: Science. 2010 Sep 3;329(5996):1197-201
references: 20813953
references: Am J Clin Pathol. 2007 Apr;127(4):572-9
references: 17369132
references: J Biol Chem. 2000 Feb 4;275(5):3206-12
references: 10652306
references: EMBO J. 2004 Dec 8;23(24):4792-801
references: 15538389
references: J Med Genet. 2000 Oct;37(10):741-5
references: 11015450
references: Cancer Res. 2005 Apr 15;65(8):3470-8
references: 15833883
references: J Biol Chem. 2006 Dec 1;281(48):37069-80
references: 16982625
references: Oncogene. 2011 Jan 20;30(3):334-45
references: 20856203
references: J Biol Chem. 2004 Jun 25;279(26):27440-9
references: 15084601
references: Mol Cell. 2003 Oct;12(4):817-28
references: 14580334
references: Cancer Sci. 2010 Oct;101(10):2137-44
references: 20608934
references: Cancer Res. 2011 May 15;71(10):3482-93
references: 21444673
references: J Biol Chem. 2002 Aug 9;277(32):29197-209
references: 12015308
references: J Biol Chem. 1999 Jan 8;274(2):584-94
references: 9872992
references: J Biol Chem. 2009 May 8;284(19):13202-12
references: 19265191
references: Am J Respir Cell Mol Biol. 2005 Nov;33(5):438-46
references: 16002577
references: J Natl Cancer Inst. 2009 Aug 19;101(16):1141-55
references: 19638505
references: Mol Pharmacol. 2008 Jan;73(1):235-42
references: 17951357
references: Prostate. 2002 Jun 1;51(4):268-75
references: 11987155