Induction of apoptosis by stomach cancer-associated protein-tyrosine phosphatase-1.
Stomach cancer-associated protein-tyrosine phosphatase-1 (SAP-1), a transmembrane-type protein-tyrosine phosphatase, is thought to inhibit integrin signaling by mediating the dephosphorylation of focal adhesion-associated proteins. Adenovirus-mediated overexpression of wild-type SAP-1, but not that of a catalytically inactive mutant of this enzyme, has now been shown to induce apoptosis in NIH 3T3 fibroblasts. This effect of SAP-1 was dependent on cellular caspase activities and was preceded by inactivation of two serine-threonine protein kinases, Akt and integrin-linked kinase (ILK), both of which function downstream of phosphoinositide (PI) 3-kinase to promote cell survival. Coexpression of constitutively active forms of PI 3-kinase or Akt (which fully restored Akt and ILK activities) resulted in partial inhibition of SAP-1-induced cell death. Furthermore, expression of a dominant negative mutant of PI 3-kinase did not induce cell death as efficiently as did SAP-1, although this mutant inhibited Akt and ILK activities more effectively than did SAP-1. Overexpression of SAP-1 had no substantial effect on Ras activity. These results suggest that SAP-1 induces apoptotic cell death by at least two distinct mechanisms: inhibition of cell survival signaling mediated by PI 3-kinase, Akt, and ILK and activation of a caspase-dependent proapoptotic pathway.
Takada
Toshiyuki
T
Division of Diabetes and Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Noguchi
Tetsuya
T
Inagaki
Kenjiro
K
Hosooka
Tetsuya
T
Fukunaga
Kaoru
K
Yamao
Takuji
T
Ogawa
Wataru
W
Matozaki
Takashi
T
Kasuga
Masato
M
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000502:physiology*; D011956:Receptors, Cell Surface; D014443:Tyrosine / Q000378:metabolism; D000099200:Scaffold Protein ILK
D019869:Phosphatidylinositol 3-Kinases; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D011956:Receptors, Cell Surface; D014443:Tyrosine; D000099200:Scaffold Protein ILK; C431695:PTPRH protein, human; C000602672:SAP-1 protein, mouse