Autocrine semaphorin3A stimulates alpha2 beta1 integrin expression/function in breast tumor cells.
The axon repulsion factor semaphorin3A (SEMA3A) and its receptor neuropilin-1 (NP-1) are expressed in breast tumor cells, and function as suppressors of tumor cell migration. Based on the knowledge that both SEMA3A and the alpha2beta1 integrin suppress breast tumor cell migration, we studied the impact of SEMA3A signaling on alpha2beta1 integrin expression/function. The incubation of breast tumor cells with SEMA3A increased alpha2 and beta1 integrin levels, and stimulated tumor cell adhesion to the alpha2beta1-binding matrix protein collagen I. Conversely, reducing SEMA3A expression in breast tumor cells decreased alpha2beta1 levels and collagen adhesion. The ability of SEMA3A to increase tumor cell adhesion to collagen was dependent on both the SEMA3A receptor NP-1 and the glycogen synthase kinase-3. The incubation of breast tumor cells with SEMA3A disrupted the actin cytoskeleton, and reduced both tumor cell migratory and invasive behavior. Importantly, using an alpha2beta1-neutralizing antibody, we demonstrated that SEMA3A suppression of tumor cell migration is dependent on alpha2beta1. Our studies indicate that expression of the alpha2beta1 integrin, a suppressor of metastatic breast tumor growth, is stimulated in breast tumor cells by an autocrine SEMA3A pathway.
Pan
Hongjie
H
Department of Pathology, Duke University Medical Center, P.O. Box 3712 D.U.M.C., Durham, NC, 27710, USA.
Wanami
Luke S
LS
Dissanayake
Thusitha R
TR
Bachelder
Robin E
RE
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D019898:Autocrine Communication / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D024042:Collagen Type I; D003599:Cytoskeleton / Q000648:ultrastructure; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D038982:Integrin alpha2beta1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D039942:Neuropilin-1 / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D040121:Semaphorin-3A / Q000494:pharmacology / Q000502:physiology*
D057134:Antibodies, Neutralizing; D024042:Collagen Type I; D038982:Integrin alpha2beta1; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; C108639:SEMA3A protein, human; D040121:Semaphorin-3A; D039942:Neuropilin-1
Oncogene. 2005 Mar 17;24(12):2032-41
15688013
J Cell Biol. 2002 Apr 15;157(2):211-7
11956225
Cell. 1997 Aug 22;90(4):739-51
9288753
Am J Pathol. 1993 May;142(5):1439-48
8388172
Blood. 2005 Mar 1;105(5):1992-9
15522955
Br J Surg. 1995 Sep;82(9):1192-6
7551993
Am J Pathol. 2002 Jul;161(1):337-44
12107118
J Cell Sci. 1995 Feb;108 ( Pt 2):595-607
7769004
Cancer Res. 2003 Sep 1;63(17):5230-3
14500350
J Cell Biol. 1993 Aug;122(3):729-37
8335696
Neuron. 2000 Aug;27(2):237-49
10985345
Mol Biol Cell. 1999 Feb;10(2):271-82
9950676
J Cell Biol. 2005 Nov 21;171(4):717-28
16301336
Mol Cell Biol. 2004 Feb;24(4):1505-15
14749368
Nature. 2003 Jul 24;424(6947):391-7
12879061
Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7411-5
7638207
Mol Biol Cell. 2005 Jan;16(1):51-63
15509657
EMBO J. 1998 Apr 15;17(8):2139-47
9545227
Cell. 1997 Aug 22;90(4):753-62
9288754
J Cell Biol. 1999 Jul 12;146(1):233-42
10402473
Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5545-50
17369353
Chem Biol. 2000 Oct;7(10):793-803
11033082
Int J Oncol. 2007 May;30(5):1231-8
17390026
Am J Pathol. 1990 Oct;137(4):863-70
2221016
Blood. 2005 Aug 1;106(3):913-21
15831706
Proc Natl Acad Sci U S A. 1989 Dec;86(24):9906-10
2557634