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Beta-parvin inhibits integrin-linked kinase signaling and is downregulated in breast cancer.

Abstract
We analysed breast tumors and breast cancer cell lines for the expression of beta-parvin (ParvB), an adaptor protein that binds to the integrin-linked kinase (ILK). Quantitative RT-PCR indicated that ParvB mRNA was downregulated, by at least 60%, in four of nine breast tumors, relative to patient-matched normal mammary gland tissue. We also found that ParvB protein levels were reduced by > or =90% in five of seven advanced tumors, relative to matched normal breast tissue. Conversely, ILK protein and kinase activity levels were elevated in these tumors, suggesting that downregulation of ParvB stimulates ILK signaling. Western blot analyses indicated very low levels of ParvB protein in MDA-MB-231 and MCF7 breast cancer cells, facilitating functional studies of the effects of ParvB on ILK signaling. Expression of ParvB in MDA-MB-231 and MCF7 cells increased cell adhesion to collagen. ParvB inhibited ILK kinase activity, anchorage-independent cell growth and in vitro matrigel invasion by MDA-MB-231 cells. EGF-induced phosphorylation of two ILK targets, PKB (Ser473) and glycogen synthase kinase 3beta (Ser9), was also inhibited by ParvB. These results indicated that ParvB inhibits ILK signaling downstream of receptor tyrosine kinases. Our results suggest that loss of ParvB expression is a novel mechanism for upregulating ILK activity in tumors.
AuthorsPerry S Mongroo, Cameron N Johnstone, Izabela Naruszewicz, Chungyee Leung-Hagesteijn, Raphael K Sung, Leanne Carnio, Anil K Rustgi, Gregory E Hannigan
JournalOncogene (Oncogene) Vol. 23 Issue 55 Pg. 8959-70 (Nov 25 2004) ISSN: 0950-9232 [Print] England
PMID15467740 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antibodies
  • Coloring Agents
  • DNA, Complementary
  • Drug Combinations
  • Laminin
  • PARVB protein, human
  • Proteoglycans
  • RNA, Messenger
  • Recombinant Proteins
  • Tetrazolium Salts
  • Thiazoles
  • Actinin
  • matrigel
  • Epidermal Growth Factor
  • Collagen
  • integrin-linked kinase
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Protein Serine-Threonine Kinases
  • Glycogen Synthase Kinase 3
  • thiazolyl blue
Topics
  • Actinin (metabolism)
  • Adenoviridae (genetics)
  • Amino Acid Sequence
  • Antibodies (chemistry)
  • Blotting, Western
  • Breast Neoplasms (metabolism, pathology)
  • Cell Adhesion
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • Collagen (chemistry, metabolism, pharmacology)
  • Coloring Agents (pharmacology)
  • DNA, Complementary (metabolism)
  • Down-Regulation
  • Drug Combinations
  • Epidermal Growth Factor (metabolism)
  • Genes, Reporter
  • Glycogen Synthase Kinase 3 (metabolism)
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Laminin (chemistry, pharmacology)
  • Models, Genetic
  • Molecular Sequence Data
  • Phosphorylation
  • Plasmids (metabolism)
  • Protein Serine-Threonine Kinases (metabolism)
  • Protein Structure, Tertiary
  • Proteoglycans (chemistry, pharmacology)
  • RNA, Messenger (metabolism)
  • Recombinant Proteins (chemistry)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tetrazolium Salts (pharmacology)
  • Thiazoles (pharmacology)
  • Transfection
  • Two-Hybrid System Techniques
  • Up-Regulation

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