Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors.
Arterial smooth muscle cells (SMCs) are arrested in the G1 phase of the cell cycle on polymerized type I collagen fibrils, while monomer collagen supports SMC proliferation. Cyclin E-associated kinase and cyclin-dependent kinase 2 (cdk2) phosphorylation are inhibited on polymerized collagen, and levels of the cdk2 inhibitors p27Kip1 and p21Cip1/Waf1 are increased compared with SMCs on monomer collagen. p27Kip1 associates with the cyclin E-cdk2-p21Cip1/Waf1 complex in SMCs on polymerized collagen. Monovalent blocking antibodies to alpha2 integrins, integrins that mediate adhesion to both forms of collagen, mimic these effects on monomer collagen. Furthermore, polymerized collagen rapidly suppresses p70 S6 kinase, a possible regulator of p27Kip1. Thus, fibrillar collagen specifically regulates early integrin signaling that may lead to up-regulation of cdk2 inhibitors and inhibition of SMC proliferation.
Koyama
H
H
Department of Pathology, University of Washington, Seattle 98195-7470, USA.
Raines
E W
EW
Bornfeldt
K E
KE
Roberts
J M
JM
Ross
R
R
D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D001011:Aorta / Q000187:drug effects / Q000648:ultrastructure; D042846:CDC2-CDC28 Kinases; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology*; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007231:Infant, Newborn; D039421:Integrin alpha2; D016023:Integrins / Q000276:immunology; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation; D011108:Polymers; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation / Q000502:physiology
D000906:Antibodies; D015703:Antigens, CD; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D007140:Immunoglobulin Fab Fragments; D039421:Integrin alpha2; D016023:Integrins; D008869:Microtubule-Associated Proteins; D011108:Polymers; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases