RasGRP1 overexpression in T-ALL increases basal nucleotide exchange on Ras rendering the Ras/PI3K/Akt pathway responsive to protumorigenic cytokines
Copyright policy )RasGRP1 overexpression in T-ALL increases basal nucleotide exchange on Ras rendering the Ras/PI3K/Akt pathway responsive to protumorigenic cytokines
Ras GTPases are activated by RasGEFs and inactivated by RasGAPs, which stimulate the hydrolysis of RasGTP to inactive RasGDP. GTPase-impairing somatic mutations in RAS genes, such as KRAS(G12D), are among the most common oncogenic events in metastatic cancer. A different type of cancer Ras signal, driven by overexpression of the RasGEF RasGRP1 (Ras guanine nucleotide-releasing protein 1), was recently implicated in pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients and murine models, in which RasGRP1 T-ALLs expand in response to treatment with interleukins (ILs) 2, 7 and 9. Here, we demonstrate that IL-2/7/9 stimulation activates Erk and Akt pathways downstream of Ras in RasGRP1 T-ALL but not in normal thymocytes. In normal lymphocytes, RasGRP1 is recruited to the membrane by diacylglycerol (DAG) in a phospholipase C-γ (PLCγ)-dependent manner. Surprisingly, we find that leukemic RasGRP1-triggered Ras-Akt signals do not depend on acute activation of PLCγ to generate DAG but rely on baseline DAG levels instead. In agreement, using three distinct assays that measure different aspects of the RasGTP/GDP cycle, we established that overexpression of RasGRP1 in T-ALLs results in a constitutively high GTP-loading rate of Ras, which is constantly counterbalanced by hydrolysis of RasGTP. KRAS(G12D) T-ALLs do not show constitutive GTP loading of Ras. Thus, we reveal an entirely novel type of leukemogenic Ras signals that is based on a RasGRP1-driven increased in flux through the RasGTP/GDP cycle, which is mechanistically very different from KRAS(G12D) signals. Our studies highlight the dynamic balance between RasGEF and RasGAP in these T-ALLs and put forth a new model in which IL-2/7/9 decrease RasGAP activity.
- University of New Mexico United States
- Jena University Hospital Germany
- Institute of Molecular Biology Germany
- University of California, San Francisco United States
- Friedrich Schiller University Jena Germany
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (mesh), DNA-Binding Proteins (mesh), Guanosine Diphosphate (mesh), Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Mice, Phosphatidylinositol 3-Kinases, Receptors, 1103 Clinical Sciences (for), Guanine Nucleotide Exchange Factors (mesh), 2.1 Biological and endogenous factors, Childhood Leukemia (rcdc), Animals (mesh), Guanine Nucleotide Exchange Factors, Aetiology, 3101 Biochemistry and cell biology (for-2020), Child, Cancer, Diglycerides (mesh), Pediatric, Cancer (rcdc), Humans (mesh), Tumor, Blotting, Mice (mesh), Hematology, ras Proteins (mesh), Biological Sciences, 1112 Oncology and Carcinogenesis (for), Pediatric Cancer (rcdc), DNA-Binding Proteins, Cytokines, Guanosine Triphosphate (mesh), Guanosine Triphosphate, Tumor (mesh), Western, Interleukin-2 (mesh), Signal Transduction, Phosphatidylinositol 3-Kinases (mesh), Cytokine (mesh), Childhood Leukemia, Pediatric Cancer, Clinical Sciences, Oncology and Carcinogenesis, Blotting, Western, Child (mesh), Guanosine Diphosphate, Cell Line, Rare Diseases (rcdc), Diglycerides, Rare Diseases, Western (mesh), Cell Line, Tumor, 3211 Oncology and carcinogenesis (for-2020), Animals, Humans, Oncology & Carcinogenesis, Receptors, Cytokine, Cytokine, Pediatric (rcdc), 1.1 Normal biological development and functioning (hrcs-rac), Hematology (rcdc), 31 Biological Sciences (for-2020), Phospholipase C gamma, Interleukin-7, Interleukin-9, Phospholipase C gamma (mesh), 2.1 Biological and endogenous factors (hrcs-rac), Cancer (hrcs-hc), 3101 Biochemistry and Cell Biology (for-2020), Cytokines (mesh), Oncology & Carcinogenesis (science-metrix), ras Proteins, Signal Transduction (mesh), Interleukin-2, Biochemistry and Cell Biology, Proto-Oncogene Proteins c-akt, Interleukin-7 (mesh), Interleukin-9 (mesh), Proto-Oncogene Proteins c-akt (mesh)
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (mesh), DNA-Binding Proteins (mesh), Guanosine Diphosphate (mesh), Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Mice, Phosphatidylinositol 3-Kinases, Receptors, 1103 Clinical Sciences (for), Guanine Nucleotide Exchange Factors (mesh), 2.1 Biological and endogenous factors, Childhood Leukemia (rcdc), Animals (mesh), Guanine Nucleotide Exchange Factors, Aetiology, 3101 Biochemistry and cell biology (for-2020), Child, Cancer, Diglycerides (mesh), Pediatric, Cancer (rcdc), Humans (mesh), Tumor, Blotting, Mice (mesh), Hematology, ras Proteins (mesh), Biological Sciences, 1112 Oncology and Carcinogenesis (for), Pediatric Cancer (rcdc), DNA-Binding Proteins, Cytokines, Guanosine Triphosphate (mesh), Guanosine Triphosphate, Tumor (mesh), Western, Interleukin-2 (mesh), Signal Transduction, Phosphatidylinositol 3-Kinases (mesh), Cytokine (mesh), Childhood Leukemia, Pediatric Cancer, Clinical Sciences, Oncology and Carcinogenesis, Blotting, Western, Child (mesh), Guanosine Diphosphate, Cell Line, Rare Diseases (rcdc), Diglycerides, Rare Diseases, Western (mesh), Cell Line, Tumor, 3211 Oncology and carcinogenesis (for-2020), Animals, Humans, Oncology & Carcinogenesis, Receptors, Cytokine, Cytokine, Pediatric (rcdc), 1.1 Normal biological development and functioning (hrcs-rac), Hematology (rcdc), 31 Biological Sciences (for-2020), Phospholipase C gamma, Interleukin-7, Interleukin-9, Phospholipase C gamma (mesh), 2.1 Biological and endogenous factors (hrcs-rac), Cancer (hrcs-hc), 3101 Biochemistry and Cell Biology (for-2020), Cytokines (mesh), Oncology & Carcinogenesis (science-metrix), ras Proteins, Signal Transduction (mesh), Interleukin-2, Biochemistry and Cell Biology, Proto-Oncogene Proteins c-akt, Interleukin-7 (mesh), Interleukin-9 (mesh), Proto-Oncogene Proteins c-akt (mesh)
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