Discoidin domain receptor 2 mediates tumor cell cycle arrest induced by fibrillar collagen.
During malignant invasion tumor cells establish contact with extracellular matrix proteins, including fibrillar collagen. In addition to providing a physical barrier against invasion, fibrillar collagen also restricts cell proliferation. It has been assumed that the growth regulatory activity of fibrillar collagen is the result of an indirect restrictive effect on cell spreading and cytoskeletal organization. Here we provide evidence for a direct inhibitory effect of fibrillar collagen on proliferation of human melanoma and fibrosarcoma cells that involves activation of the tyrosine kinase discoidin domain receptor 2 and is independent of effects on cell spreading. Cells plated in the presence of fibrillar collagen were growth arrested in the G0/G1 phase of the cell cycle. However treatment with the tyrosine kinase inhibitor genistein, down-regulation of discoidin domain receptor 2, or collagen deglycosylation that prevents discoidin domain receptor 2 activation allowed cells to enter the cell cycle in the presence of fibrillar collagen without a requirement for spreading and actin organization. Our data provide evidence for a novel direct mechanism by which cell contact with fibrillar collagen restricts proliferation.
Wall
Steven J
SJ
Division of Hematology-Oncology and Department of Pediatrics, University of Southern California and the Saban Research Institute of Childrens Hospital, Los Angeles, California 90027, USA.
Werner
Erica
E
Werb
Zena
Z
DeClerck
Yves A
YA
D015153:Blotting, Western; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D003094:Collagen / Q000737:chemistry*; D000070818:Discoidin Domain Receptors; D015536:Down-Regulation; D005434:Flow Cytometry; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012313:RNA / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000502:physiology*; D011975:Receptors, Mitogen / Q000737:chemistry / Q000502:physiology*; D016192:Resting Phase, Cell Cycle; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D034741:RNA, Small Interfering; D011975:Receptors, Mitogen; D012313:RNA; D003094:Collagen; D019833:Genistein; D000070818:Discoidin Domain Receptors; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases