Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis
Copyright policy )Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis
Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.
- University of California, San Francisco United States
- Emory University United States
- Cleveland Clinic United States
- Indiana University United States
- Center for Cancer and Blood Disorders United States
Myeloid, rac1 GTP-Binding Protein, Carcinogenesis, Medical Physiology, Inbred C57BL, Mice, STAT5 Transcription Factor, 2.1 Biological and endogenous factors, Guanine Nucleotide Exchange Factors, T-Lymphoma Invasion and Metastasis-inducing Protein 1, Aetiology, Biology (General), Phosphorylation, Cancer, Pediatric, Leukemia, Hematology, Leukemia, Myeloid, Acute, Protein Transport, Proto-Oncogene Proteins c-kit, Mastocytosis, Signal Transduction, Childhood Leukemia, Pediatric Cancer, QH301-705.5, Protein Kinase Inhibitor, 610, Acute, 576, Rare Diseases, Mastocytosis, Systemic, Genetics, Animals, Humans, Benzothiazoles, Protein Kinase Inhibitors, Cell Proliferation, Cell Nucleus, Phenylurea Compounds, Systemic, Survival Analysis, Mice, Inbred C57BL, fms-Like Tyrosine Kinase 3, p21-Activated Kinases, Focal Adhesion Protein-Tyrosine Kinases, Mutation, Mutant Proteins, Biochemistry and Cell Biology
Myeloid, rac1 GTP-Binding Protein, Carcinogenesis, Medical Physiology, Inbred C57BL, Mice, STAT5 Transcription Factor, 2.1 Biological and endogenous factors, Guanine Nucleotide Exchange Factors, T-Lymphoma Invasion and Metastasis-inducing Protein 1, Aetiology, Biology (General), Phosphorylation, Cancer, Pediatric, Leukemia, Hematology, Leukemia, Myeloid, Acute, Protein Transport, Proto-Oncogene Proteins c-kit, Mastocytosis, Signal Transduction, Childhood Leukemia, Pediatric Cancer, QH301-705.5, Protein Kinase Inhibitor, 610, Acute, 576, Rare Diseases, Mastocytosis, Systemic, Genetics, Animals, Humans, Benzothiazoles, Protein Kinase Inhibitors, Cell Proliferation, Cell Nucleus, Phenylurea Compounds, Systemic, Survival Analysis, Mice, Inbred C57BL, fms-Like Tyrosine Kinase 3, p21-Activated Kinases, Focal Adhesion Protein-Tyrosine Kinases, Mutation, Mutant Proteins, Biochemistry and Cell Biology
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