Pro-adhesive and chemotactic activities of thrombospondin-1 for breast carcinoma cells are mediated by alpha3beta1 integrin and regulated by insulin-like growth factor-1 and CD98.
Thrombospondin-1 (TSP1) is a matricellular protein that displays both pro- and anti-adhesive activities. Binding to sulfated glycoconjugates mediates most high affinity binding of soluble TSP1 to MDA-MB-435 cells, but attachment and spreading of these cells on immobilized TSP1 is primarily beta1 integrin-dependent. The integrin alpha3beta1 is the major mediator of breast carcinoma cell adhesion and chemotaxis to TSP1. This integrin is partially active in MDA-MB-435 cells but is mostly inactive in MDA-MB-231 and MCF-7 cells, which require beta1 integrin activation to induce spreading on TSP1. Integrin-mediated cell spreading on TSP1 is accompanied by extension of filopodia containing beta1 integrins. TSP1 binding activity of the alpha3beta1 integrin is not stimulated by CD47-binding peptides from TSP1 or by protein kinase C activation, which activate alphavbeta3 integrin function in the same cells. In MDA-MB-231 but not MDA-MB-435 cells, this integrin is activated by pertussis toxin, whereas serum, insulin, insulin-like growth factor-1, and ligation of CD98 increase activity of this integrin in both cell lines. Serum stimulation is accompanied by increased surface expression of CD98, whereas insulin-like growth factor-1 does not increase CD98 expression. Thus, the pro-adhesive activity of TSP1 for breast carcinoma cells is controlled by several signals that regulate activity of the alpha3beta1 integrin.
Chandrasekaran
S
S
Laboratory of Pathology, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Guo
N H
NH
Rodrigues
R G
RG
Kaiser
J
J
Roberts
D D
DD
D015703:Antigens, CD / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology; D027261:Fusion Regulatory Protein-1; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D039201:Integrin alpha3beta1; D016023:Integrins / Q000502:physiology*; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D002352:Carrier Proteins; D027261:Fusion Regulatory Protein-1; D039201:Integrin alpha3beta1; D016023:Integrins; D019700:Thrombospondin 1; D007334:Insulin-Like Growth Factor I; D019204:GTP-Binding Proteins