scholarly journals Role of Dok-1 and Dok-2 in Leukemia Suppression

2004 ◽  
Vol 200 (12) ◽  
pp. 1689-1695 ◽  
Author(s):  
Masaru Niki ◽  
Antonio Di Cristofano ◽  
Mingming Zhao ◽  
Hiroaki Honda ◽  
Hisamaru Hirai ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Cellular Proliferation ◽  
Myelogenous Leukemia ◽  
Myeloproliferative Disease ◽  
Kinase Activation ◽  
Abl Tyrosine Kinase ◽  
Long Latency

Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210bcr/abl oncoprotein that shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Although several p210bcr/abl substrates have been identified, their relevance in the pathogenesis of the disease is unclear. We have identified a family of proteins, Dok (downstream of tyrosine kinase), coexpressed in hematopoietic progenitor cells. Members of this family such as p62dok(Dok-1) and p56dok-2(Dok-2) associate with the p120 rasGTPase-activating protein (rasGAP) upon phosphorylation by p210bcr/abl as well as receptor and nonreceptor tyrosine kinases. Here, we report the generation and characterization of single and double Dok-1 or Dok-2 knockout (KO) mutants. Single KO mice displayed normal steady-state hematopoiesis. By contrast, concomitant Dok-1 and Dok-2 inactivation resulted in aberrant hemopoiesis and Ras/MAP kinase activation. Strikingly, all Dok-1/Dok-2 double KO mutants spontaneously developed transplantable CML-like myeloproliferative disease due to increased cellular proliferation and reduced apoptosis. Furthermore, Dok-1 or Dok-2 inactivation markedly accelerated leukemia and blastic crisis onset in Tec-p210bcr/abl transgenic mice known to develop, after long latency, a myeloproliferative disorder resembling human CML. These findings unravel the critical and unexpected role of Dok-1 and Dok-2 in tumor suppression and control of the hematopoietic compartment homeostasis.

Critical Role of Dok-1 and Dok-2 in Leukemia Suppression.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2951-2951
Author(s):  
Masaru Niki ◽  
Antonio Di Cristofano ◽  
Mingming Zhao ◽  
Hisamaru Hirai ◽  
Linda Van Aelst ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Cellular Proliferation ◽  
Critical Role ◽  
Myelogenous Leukemia ◽  
Kinase Activation ◽  
Abl Tyrosine Kinase ◽  
Long Latency

Abstract Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210bcr/abl oncoprotein which shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. While several p210bcr/abl substrates have been identified, their relevance in the pathogenesis of the disease is unclear. We have identified a family of proteins, Dok (downstream of tyrosine kinase), coexpressed in hematopoietic progenitor cells. Members of this family such as p62dok (Dok-1) and p56dok-2 (Dok-2) associate with the p120 rasGTPase-activating protein (rasGAP) upon phosphorylation by p210bcr/abl as well as receptor and non-receptor tyrosine kinases. Here we report the generation and characterization of single and double Dok-2 or Dok-1/Dok-2 KO mutants. Single KO mice displayed normal steady state hematopoiesis. By contrast, concomitant Dok-1 and Dok-2 inactivation resulted in aberrant hemopoiesis and Ras/MAP kinase activation. Strikingly, all Dok-1/Dok-2 double KO mutants spontaneously developed transplantable CML-like leukemia due to increased cellular proliferation and reduced apoptosis. Furthermore, Dok-1 or Dok-2 inactivation markedly accelerated leukemia and blastic crisis onset in Tec-p210bcr/abl transgenic mice known to develop, after long latency, a myeloproliferative disorder resembling human CML. These findings unravel the critical and unexpected role of Dok-1 and 2 in tumor suppression and control of the hematopoietic compartment homeostasis.

scholarly journals Role of Dok-1 and Dok-2 in Myeloid Homeostasis and Suppression of Leukemia

2004 ◽  
Vol 200 (12) ◽  
pp. 1681-1687 ◽  
Author(s):  
Tomoharu Yasuda ◽  
Masaki Shirakata ◽  
Atsushi Iwama ◽  
Asuka Ishii ◽  
Yasuhiro Ebihara ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Myeloid Cells ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Myeloproliferative Disease ◽  
Akt Activation ◽  
Docking Proteins ◽  
Cytokine Stimulation ◽  
Deficient Mice

Dok-1 and Dok-2 are closely related rasGAP-associated docking proteins expressed preferentially in hematopoietic cells. Although they are phosphorylated upon activation of many protein tyrosine kinases (PTKs), including those coupled with cytokine receptors and oncogenic PTKs like Bcr-Abl, their physiological roles are largely unidentified. Here, we generated mice lacking Dok-1 and/or Dok-2, which included the double-deficient mice succumbed to myeloproliferative disease resembling human chronic myelogenous leukemia (CML) and chronic myelomonocytic leukemia. The double-deficient mice displayed medullary and extramedullary hyperplasia of granulocyte/macrophage progenitors with leukemic potential, and their myeloid cells showed hyperproliferation and hypo-apoptosis upon treatment and deprivation of cytokines, respectively. Consistently, the mutant myeloid cells showed enhanced Erk and Akt activation upon cytokine stimulation. Moreover, loss of Dok-1 and/or Dok-2 induced blastic transformation of chronic phase CML-like disease in mice carrying the bcr-abl gene, a cause of CML. These findings demonstrate that Dok-1 and Dok-2 are key negative regulators of cytokine responses and are essential for myeloid homeostasis and suppression of leukemia.

Src tyrosine kinase is the trigger but not the mediator of ischemic preconditioning

2001 ◽  
Vol 281 (3) ◽  
pp. H1066-H1074 ◽  
Author(s):  
Reiji Hattori ◽  
Hajime Otani ◽  
Takamichi Uchiyama ◽  
Hiroji Imamura ◽  
Jianhua Cui ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Ischemic Preconditioning ◽  
Tyrosine Kinases ◽  
Src Kinase ◽  
Src Tyrosine Kinase ◽  
Kinase Activation ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Src Activation

The signal cascade that triggers and mediates ischemic preconditioning (IPC) remains unclear. The present study investigated the role of the Src family of tyrosine kinases in IPC. Isolated and buffer-perfused rat hearts underwent IPC with three cycles of 5-min ischemia and 5-min reperfusion, followed by 30-min ischemia and 120-min reperfusion. The Src tyrosine kinase family-selective inhibitor PP1 was administered between 45 and 30 min before ischemia (early PP1 treatment) or for 15 min before IPC [early PP1-preconditioning (PC) treatment]. PP1 was also administered for 5 min before the sustained ischemia (late PP1 treatment) or after IPC (late PP1-PC treatment). Src kinase was activated after 30 min of ischemia in both the membrane and cytosolic fractions. Src kinase was also activated by IPC but was attenuated after the sustained ischemia. Early and late PP1 treatment inhibited Src activation after the sustained ischemia and reduced infarct size. Early PP1-PC inhibited Src activation after IPC but not after the sustained ischemia and blocked cardioprotection afforded by IPC. Late PP1-PC treatment abrogated IPC-induced activation of Src and protein kinase C (PKC)-ε in the membrane but not in the cytosolic fraction. This treatment modality abrogated Src activation after the sustained ischemia and failed to block cardioprotection afforded by IPC. These results suggest that Src kinase activation mediates ischemic injury but triggers IPC in the position either upstream of or parallel to membrane-associated PKC-ε.

scholarly journals Tyrphostin-induced inhibition of p210bcr-abl tyrosine kinase activity induces K562 to differentiate

Blood ◽  
1993 ◽  
Vol 82 (12) ◽  
pp. 3524-3529 ◽  
Author(s):  
M Anafi ◽  
A Gazit ◽  
A Zehavi ◽  
Y Ben-Neriah ◽  
A Levitzki
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Kinase Activity ◽  
Therapeutic Potential ◽  
Autologous Bone Marrow Transplantation ◽  
Philadelphia Chromosome ◽  
Autologous Bone Marrow ◽  
Myelogenous Leukemia ◽  
Tyrosine Kinase Activity ◽  
Abl Tyrosine Kinase

Abstract We report on the potency of two Tyrphostin tyrosine kinase blockers, AG 1112 and AG 568, to inhibit p210bcr-abl tyrosine kinase activity in K562 cells, concomitant with the induction of erythroid differentiation. AG 568 and especially AG 1112 represent a specific group of nontoxic protein tyrosine kinase blockers among more than 1,400 tested. These compounds possess therapeutic potential for purging Philadelphia chromosome-positive cells in preparation for autologous bone marrow transplantation in chronic myelogenous leukemia.

scholarly journals Tyrphostin-induced inhibition of p210bcr-abl tyrosine kinase activity induces K562 to differentiate

Blood ◽  
1993 ◽  
Vol 82 (12) ◽  
pp. 3524-3529 ◽  
Author(s):  
M Anafi ◽  
A Gazit ◽  
A Zehavi ◽  
Y Ben-Neriah ◽  
A Levitzki
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Kinase Activity ◽  
Therapeutic Potential ◽  
Autologous Bone Marrow Transplantation ◽  
Philadelphia Chromosome ◽  
Autologous Bone Marrow ◽  
Myelogenous Leukemia ◽  
Tyrosine Kinase Activity ◽  
Abl Tyrosine Kinase

We report on the potency of two Tyrphostin tyrosine kinase blockers, AG 1112 and AG 568, to inhibit p210bcr-abl tyrosine kinase activity in K562 cells, concomitant with the induction of erythroid differentiation. AG 568 and especially AG 1112 represent a specific group of nontoxic protein tyrosine kinase blockers among more than 1,400 tested. These compounds possess therapeutic potential for purging Philadelphia chromosome-positive cells in preparation for autologous bone marrow transplantation in chronic myelogenous leukemia.

Src induces morphological changes in A431 cells that resemble epidermal differentiation through an SH3- and Ras-independent pathway

1999 ◽  
Vol 112 (17) ◽  
pp. 2913-2924
Author(s):  
F. Jin ◽  
A.B. Reynolds ◽  
M.D. Hines ◽  
P.J. Jensen ◽  
K.R. Johnson ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
Morphological Changes ◽  
Sh2 Domain ◽  
Epidermal Differentiation ◽  
A431 Cells ◽  
Src Family Tyrosine Kinases

The role of Src family tyrosine kinases in cellular proliferation is well established; however, their role in cellular differentiation is less well understood. In this study we have investigated the role played by Src in the differentiation of squamous epithelial cells. Transfection of activated Src into A431 cells resulted in morphological changes that resembled epidermal differentiation. When we used Src mutants to characterize the observed phenotypic changes, we found that protein tyrosine kinase activity, correct membrane localization and the activity of the SH2 domain were required, but the SH3 domain was not. Furthermore, downstream activity of Ras was not required for the Src-mediated changes in A431 cells.

Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis

Blood ◽  
2004 ◽  
Vol 104 (9) ◽  
pp. 2912-2918 ◽  
Author(s):  
Ian J. Griswold ◽  
Lei J. Shen ◽  
Paul La Rosée ◽  
Shadmehr Demehri ◽  
Michael C. Heinrich ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Myelogenous Leukemia ◽  
Significant Activity ◽  
Kinase Activation ◽  
Molecule Inhibitor ◽  
Acute Myelogenous ◽  
Normal Human

Abstract Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady-state conditions, after chemotherapy-induced myelosuppression, and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate in BCR-ABL–positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols.

scholarly journals Role of Protein Tyrosine Kinase p53/56lyn in Diminished Lipopolysaccharide Priming of Formylmethionylleucyl- phenylalanine-Induced Superoxide Production in Human Newborn Neutrophils

2004 ◽  
Vol 72 (11) ◽  
pp. 6455-6462 ◽  
Author(s):  
Sen Rong Yan ◽  
David M. Byers ◽  
Robert Bortolussi
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Critical Role ◽  
Polymorphonuclear Neutrophils ◽  
Protein Tyrosine Kinases ◽  
Protein Tyrosine ◽  
Adult Cells

ABSTRACT Human newborns are more susceptible than adults to bacterial infection. With gram-negative bacteria, this may be due to a diminished response of newborn leukocytes to lipopolysaccharide (LPS). Since protein tyrosine kinase inhibition abolishes LPS priming in adult cells, we hypothesized that protein tyrosine kinases may have a critical role in LPS priming of polymorphonuclear neutrophils (PMNs) and that newborn PMNs may have altered protein tyrosine kinase activities. In the present study, we investigated the role of src family protein tyrosine kinases in the LPS response of newborn PMNs compared to adult cells. In a respiratory assay, the LPS-primed increase in formylmethionylleucylphenylalanine (fMLP)-triggered O2 − release by adult PMNs was greatly decreased by PP1 [4-amino-5-(4-methyphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine], a src kinase inhibitor, to the level of untreated newborn PMNs, in which LPS failed to prime. LPS activated the src-like kinases p59hck (HCK) and p58fgr (FGR) in both adult and newborn PMNs but increased the activation of p53/56 lyn (LYN) only in adult cells. In newborn PMNs, LYN was highly phosphorylated independent of LPS. We evaluated subcellular fractions of PMNs and found that the phosphorylated form of LYN was mainly in the Triton-extractable, cytosolic fraction in adult PMNs, while in newborn cells it was located mainly in Triton-insoluble, granule- and membrane-associated fractions. In contrast, the phosphorylated mitogen-activated protein kinases ERK1/2 and p38 were mainly detected in the cytosol in both adult and newborn PMNs. These data indicate a role for LYN in the regulation of LPS priming. The trapping of phosphorylated LYN in the membrane-granule fraction in newborn PMNs may contribute to the deficiency of newborn cells in responding to LPS stimulation.

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