PTEN gene and integrin signaling in cancer.
Integrins are major adhesion- and signaling-receptor proteins that mediate cell migration and invasion. They also trigger a variety of signal transduction pathways and regulate cytoskeletal organization, specific gene expression, growth control, and apoptosis (programmed cell death). Consequently, integrins are thought to play important roles in embryonic development and in the biology of cancers. The functions of integrins can be negatively regulated by the recently discovered tumor suppressor PTEN, a protein with homology to protein tyrosine phosphatases and tensin. The PTEN gene is mutated in a wide range of human cancers. PTEN inhibits cell migration and invasion by directly dephosphorylating two key tyrosine-phosphorylated proteins, thereby antagonizing interactions of integrins with the extracellular matrix and integrin-triggered signaling pathways. Other studies demonstrate important roles for PTEN in dephosphorylating a key signal transduction lipid. In the absence of PTEN, this lipid signal transduction pathway can protect tumor cells from apoptosis. Thus, PTEN appears to be a unique tumor suppressor-with both lipid phosphatase and protein tyrosine phosphatase activities-that negatively regulates cell interactions with the extracellular matrix and that maintains cell sensitivity to apoptosis, e.g., after loss of cell contact with the extracellular matrix. The complex signal transduction pathways regulated by PTEN are described in this review. PTEN and the signaling pathways it regulates may provide novel targets for potential therapy.
Tamura
M
M
Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA.
Gu
J
J
Tran
H
H
Yamada
K M
KM
D015815:Cell Adhesion Molecules / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016147:Genes, Tumor Suppressor / Q000235:genetics; D005910:Glioma / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000070876:Tensins; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D015815:Cell Adhesion Molecules; D016023:Integrins; D008840:Microfilament Proteins; D000070876:Tensins; D025521:Tumor Suppressor Proteins; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human