Tissue inhibitor of metalloproteinases-1 signalling pathway leading to erythroid cell survival.
Tissue inhibitors of metalloproteinases (TIMP) are specific inhibitors of matrix metalloproteinases (MMPs) and thus participate in maintaining the balance between extracellular matrix deposition and degradation in several physio-pathological processes. Nevertheless, TIMP must be regarded as multifunctional proteins involved in cell growth, angiogenesis and apoptosis. The molecular mechanisms induced by TIMP remain largely unknown. In the present study, we provide evidence that TIMP-1 induces a significant anti-apoptotic effect in the human erythroleukaemic cell line UT-7 and in the murine myeloid cell line 32D. Using specific kinases inhibitors, we show that TIMP-1-mediated cell survival is dependent upon Janus kinase (JAK) 2 and phosphoinositide 3-kinase (PI 3-kinase) activities. By transient transfection of dominant-negative Akt in UT-7 cells, we demonstrate that this kinase is crucial for the TIMP-1 anti-apoptotic effect. Moreover, TIMP-1 enhances specific phosphorylation of both Akt and Bad (Bcl-2/Bcl-X(L)-antagonist, causing cell death) in a PI 3-kinase-dependent manner and, besides, controls the level of the anti-apoptotic protein Bcl-X(L). We conclude that TIMP-1 induces haematopoietic cell survival via the JAK2/PI 3-kinase/Akt/Bad pathway.
Lambert
Elise
E
Laboratoire de Biochimie, CNRS FRE-2534, IFR53 Biomolécules, UFR Sciences Exactes et Naturelles et UFR Médecine, BP 1039, Université de Reims Champagne-Ardenne, France.
Boudot
Cédric
C
Kadri
Zahra
Z
Soula-Rothhut
Mahdhia
M
Sowa
Marie-Line
ML
Mayeux
Patrick
P
Hornebeck
William
W
Haye
Bernard
B
Petitfrere
Emmanuelle
E
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2; D004915:Leukemia, Erythroblastic, Acute; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D022423:Myeloid Cells / Q000166:cytology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D014162:Transfection
D002867:Chromones; D004791:Enzyme Inhibitors; D053614:Janus Kinase 2; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; C494918:AKT1 protein, human