Functions and mechanisms of action of CCN matricellular proteins.
Members of the CCN (CYR61/CTGF/NOV) family have emerged as dynamically expressed, extracellular matrix-associated proteins that play critical roles in cardiovascular and skeletal development, injury repair, fibrotic diseases and cancer. The synthesis of CCN proteins is highly inducible by serum growth factors, cytokines, and environmental stresses such as hypoxia, UV exposure, and mechanical stretch. Consisting of six secreted proteins in vertebrate species, CCNs are typically comprised of four conserved cysteine-rich modular domains. They function primarily through direct binding to specific integrin receptors and heparan sulfate proteoglycans, thereby triggering signal transduction events that culminate in the regulation of cell adhesion, migration, proliferation, gene expression, differentiation, and survival. CCN proteins can also modulate the activities of several growth factors and cytokines, including TGF-beta, TNFalpha, VEGF, BMPs, and Wnt proteins, and may thereby regulate a broad array of biological processes. Recent studies have uncovered novel CCN activities unexpected for matricellular proteins, including their ability to induce apoptosis as cell adhesion substrates, to dictate the cytotoxicity of inflammatory cytokines such as TNFalpha, and to promote hematopoietic stem cell self-renewal. As potent regulators of angiogenesis and chondrogenesis, CCNs are essential for successful cardiovascular and skeletal development during embryogenesis. In the adult, the expression of CCN proteins is associated with injury repair and inflammation, and has been proposed as diagnostic or prognostic markers for diabetic nephropathy, hepatic fibrosis, systemic sclerosis, and several types of cancer. Targeting CCN signaling pathways may hold promise as a strategy of rational therapeutic design.
Chen
Chih-Chiun
CC
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL 60607, United States.
Lau
Lester F
LF
D000818:Animals; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism / Q000502:physiology; D006801:Humans; D015398:Signal Transduction
D055511:CCN Intercellular Signaling Proteins
Circ Res. 2005 Jul 22;97(2):125-34
15976312
J Biol Chem. 2003 Mar 28;278(13):11465-70
12529380
J Appl Physiol (1985). 2007 Oct;103(4):1395-401
17673559
FEBS J. 2006 Aug;273(16):3639-49
16856934
Exp Cell Res. 1997 May 25;233(1):63-77
9184077
J Biol Chem. 2001 Apr 27;276(17):14187-94
11297518
Mol Cancer Ther. 2006 May;5(5):1108-16
16731742
J Bone Miner Res. 2000 Jun;15(6):1014-23
10841170
Am J Pathol. 2003 Jan;162(1):219-31
12507905
Circulation. 2002 Jul 9;106(2):254-60
12105167
Am J Physiol Renal Physiol. 2004 Dec;287(6):F1223-32
15315937
J Biol Chem. 2000 Aug 11;275(32):24953-61
10821835
J Biol Chem. 2007 Nov 23;282(47):34594-604
17905740
J Cell Physiol. 2003 Jul;196(1):51-62
12767040
Lab Invest. 2002 Jun;82(6):767-74
12065687
Nucleic Acids Res. 1991 Jun 25;19(12):3261-7
2062642
J Biochem. 1999 Jul;126(1):137-45
10393331
Cell Signal. 2008 Aug;20(8):1409-14
18296024
Endocrinology. 2001 Jun;142(6):2540-8
11356703
J Biol Chem. 2004 May 28;279(22):23098-103
15044479
J Am Soc Nephrol. 2004 Jun;15(6):1430-40
15153554
Gene Ther. 2007 May;14(10):790-803
17344905
Cancer Res. 2006 Jun 1;66(11):5816-27
16740721
Endocrinology. 2007 Dec;148(12):5761-8
17823253
J Cell Biol. 1991 Sep;114(6):1285-94
1654338
Endocrinology. 2008 Sep;149(9):4374-81
18535099
Mol Cell Biol. 2008 Apr;28(7):2391-413
18172013
BMC Dev Biol. 2008 Feb 20;8:18
18289368
Development. 2003 Jun;130(11):2429-41
12702657
J Biol Chem. 2004 Dec 31;279(53):55675-81
15492009
J Diabetes Complications. 2008 Jul-Aug;22(4):284-94
18413184
Vitam Horm. 2005;70:69-103
15727802
Proc Natl Acad Sci U S A. 1998 May 26;95(11):6355-60
9600969
Hum Mol Genet. 1997 Jan;6(1):117-21
9002679
Cancer Res. 2005 Oct 1;65(19):8887-95
16204060
Nat Cell Biol. 2002 Aug;4(8):599-604
12134160
Dev Dyn. 2008 Feb;237(2):485-93
18213577
J Biol Chem. 2004 Jun 4;279(23):24015-23
15044484
Endocrinology. 2000 Jan;141(1):264-73
10614647
J Biol Chem. 2001 Dec 14;276(50):47329-37
11584015
Development. 2003 Jun;130(12):2779-91
12736220
FASEB J. 2007 Oct;21(12):3355-68
17554073
J Bone Miner Res. 2006 Jul;21(7):1045-59
16813525
Oncogene. 2002 Nov 21;21(53):8178-85
12444554
Nat Genet. 1999 Sep;23(1):94-8
10471507
Hepatol Res. 2003 May;26(1):1-9
12787797
J Biol Chem. 2004 Oct 15;279(42):44177-87
15322081
J Cell Sci. 2006 Dec 1;119(Pt 23):4803-10
17130294
Mol Hum Reprod. 2006 Jun;12(6):389-99
16675545
Circ Res. 2006 Oct 27;99(9):961-9
17023674
Wound Repair Regen. 2004 Mar-Apr;12(2):205-16
15086772
J Biol Chem. 2002 Sep 27;277(39):36288-95
12114504
Exp Cell Res. 1999 Apr 10;248(1):44-57
10094812
Am J Respir Cell Mol Biol. 2004 Nov;31(5):510-6
15256388
J Clin Endocrinol Metab. 2008 May;93(5):1893-900
18319310
Endocrinology. 2008 May;149(5):2261-9
18202125
Curr Opin Cell Biol. 2002 Oct;14(5):608-16
12231357
Mol Biol Cell. 2004 Dec;15(12):5635-46
15371538
Mol Pathol. 2003 Apr;56(2):127-8
12665631
Hum Gene Ther. 2002 Aug 10;13(12):1461-70
12215267
J Biol Chem. 2003 Jun 27;278(26):24200-8
12695522
Biochem Biophys Res Commun. 2000 Oct 22;277(2):448-54
11032743
J Biol Chem. 2002 Oct 25;277(43):41220-9
12149257
Bone. 2006 May;38(5):671-7
16311085
Kidney Int. 2008 Feb;73(4):446-55
18075496
FEBS Lett. 1993 Jul 26;327(2):125-30
7687569
Mol Cell Biol. 1992 Jan;12(1):10-21
1309586
Angiogenesis. 2007;10(1):1-11
17149534
Dev Dyn. 2004 Nov;231(3):542-50
15376321
J Biol Chem. 2007 Dec 14;282(50):36571-81
17951630
J Exp Med. 1998 Feb 2;187(3):289-96
9449709
Am J Pathol. 2006 Aug;169(2):482-90
16877350
J Biol Chem. 2003 Sep 5;278(36):33801-8
12826661
Dev Dyn. 2004 Sep;231(1):136-47
15305294
J Cell Biol. 2005 Nov 7;171(3):559-68
16275757
EMBO J. 2007 Mar 7;26(5):1257-67
17318182
J Biol Chem. 2003 Nov 14;278(46):45651-60
12939282
J Biol Chem. 2001 Jun 15;276(24):21943-50
11287419
Nat Rev Immunol. 2003 Sep;3(9):745-56
12949498
Dev Biol. 1997 Dec 15;192(2):492-508
9441684
Hepatology. 2008 Mar;47(3):996-1004
18167060
J Biol Chem. 2005 Mar 4;280(9):8229-37
15611078
J Mol Cell Cardiol. 2004 Aug;37(2):603-6
15276029
Endocrinology. 2002 Apr;143(4):1441-50
11897702
Oncogene. 1997 Apr 10;14(14):1753-7
9135077
J Biol Chem. 2001 Mar 30;276(13):10443-52
11120741
Cell Growth Differ. 1992 Sep;3(9):645-54
1419914
Development. 2004 May;131(9):2137-47
15105373
Mol Cell Biol. 2006 Apr;26(8):2955-64
16581771
J Biol Chem. 2004 Dec 31;279(53):55958-68
15496414
Mol Cell Biol. 2005 Jan;25(1):414-21
15601861
Circulation. 2004 May 11;109(18):2227-33
15117851
Int J Med Microbiol. 2008 Apr;298(3-4):231-43
17765657
J Biol Chem. 1998 Jan 30;273(5):3090-6
9446626
Thromb Haemost. 2004 Apr;91(4):755-60
15045137
Endocr Rev. 1999 Apr;20(2):189-206
10204117
J Invest Dermatol. 1996 Sep;107(3):404-11
8751978
J Biol Chem. 2004 Mar 5;279(10):8848-55
14684735
Trends Biochem Sci. 2006 May;31(5):268-75
16603362
N Engl J Med. 2007 Sep 20;357(12):1210-20
17881752
Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14717-22
9843955
Mol Cell Biol. 1998 Oct;18(10):6131-41
9742130
J Cell Commun Signal. 2007 Dec;1(3-4):159-64
18568428
Arthritis Res Ther. 2006;8(2):R36
16469114
Endocr Relat Cancer. 2003 Jun;10(2):141-52
12790776
J Biol Chem. 1999 Aug 20;274(34):24321-7
10446209
Blood. 2002 Jun 15;99(12):4457-65
12036876
J Rheumatol. 2003 Apr;30(4):755-9
12672195
J Bone Miner Res. 2004 Aug;19(8):1308-19
15231019
J Natl Cancer Inst. 2004 Mar 3;96(5):364-75
14996858
FASEB J. 2002 Feb;16(2):219-21
11744618
J Biol Chem. 2001 Nov 2;276(44):40659-67
11518710
J Biol Chem. 2004 Oct 15;279(42):44166-76
15308622
Endocrinology. 2001 Jun;142(6):2549-57
11356704
Diabetes Care. 2008 Jun;31(6):1177-82
18344285
Oncogene. 1998 Feb 12;16(6):747-54
9488038
Cells Tissues Organs. 2007;185(1-3):95-9
17587813
J Virol. 2004 Dec;78(24):13479-88
15564459
Cell Commun Signal. 2005 Mar 17;3(1):5
15773998
Endocrinology. 1998 Apr;139(4):1761-70
9528960
Cancer Cell. 2003 Jun;3(6):537-49
12842083
J Cell Physiol. 1999 Oct;181(1):153-9
10457363
Mol Cell Biol. 1996 Apr;16(4):1326-34
8657105
Hepatol Res. 2003 Nov;27(3):214-220
14585398
Mol Cell Biol. 1990 Jul;10(7):3569-77
2355916
Arterioscler Thromb Vasc Biol. 2008 Jun;28(6):1077-83
18388330
DNA Cell Biol. 1991 May;10(4):293-300
2029337
Mol Cell Biol. 1999 Apr;19(4):2958-66
10082563
J Biol Chem. 2006 Apr 21;281(16):10715-26
16484225
J Biol Chem. 2001 Dec 14;276(50):47599-607
11598131
Bone. 2002 Oct;31(4):441-7
12398938
J Clin Invest. 2007 Oct;117(10):3075-86
17823661
Cell Growth Differ. 1991 Jul;2(7):351-7
1782153
Gastroenterology. 2005 Jan;128(1):9-23
15633118
J Cell Physiol. 2003 Aug;196(2):265-75
12811819
Circ Res. 2007 Feb 16;100(3):372-80
17234971
Mol Cell Biol. 2002 Dec;22(24):8709-20
12446788
QJM. 2005 Jul;98(7):485-92
15955800
Blood. 2007 Aug 1;110(3):877-85
17429007
Clin Cancer Res. 2005 Oct 15;11(20):7243-54
16243794
Mol Biol Cell. 1993 Jun;4(6):637-45
8374172
J Biol Chem. 2007 Sep 14;282(37):26746-26753
17626014
J Biol Chem. 2007 Jul 6;282(27):19762-72
17500060
Oncogene. 2006 Feb 16;25(7):1099-110
16247469
Oncogene. 2005 Jan 27;24(5):761-79
15592521
J Gene Med. 2006 Jul;8(7):889-900
16652398
FASEB J. 2004 Mar;18(3):469-79
15003992
J Biol Chem. 2002 Aug 16;277(33):29399-405
12050162
J Biochem. 2004 Sep;136(3):279-82
15598883
J Biol Chem. 2001 Dec 14;276(50):47709-14
11598125
Int Rev Cytol. 2007;257:1-41
17280894
J Biol Chem. 2002 Nov 29;277(48):46248-55
12364323
J Biol Chem. 2003 Apr 11;278(15):13008-15
12571253
Science. 2007 Apr 27;316(5824):590-3
17463287
Annu Rev Cell Dev Biol. 2006;22:591-621
16824013
Am J Physiol Renal Physiol. 2007 Jul;293(1):F157-65
17376761
Mol Cell Biol. 2007 Dec;27(24):8454-65
17908800