title: c-Src activation through a TrkA and c-Src interaction is essential for cell proliferation and hematological malignancies.
abstract: Although the kinase receptor TrkA may play an important role in acute myeloid leukemia (AML), its involvement in other types of leukemia has not been reported. Furthermore, how it contributes to leukemogenesis is unknown. Here, we describe a molecular network that is important for TrkA function in leukemogenesis. We found that TrkA is frequently overexpressed in other types of leukemia such as acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) including AML. In addition, TrkA was overexpressed in patients with MDS or secondary AML evolving from MDS. TrkA induced significant hematological malignancies by inducing PLK-1 and Twist-1, and enhanced survival and proliferation of leukemia, which was correlated with activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway. Moreover, endogenous TrkA associated with c-Src complexes was detected in leukemia. Suppression of c-Src activation by TrkA resulted in markedly decreased expression of PLK-1 and Twist-1 via suppressed activation of Akt/mTOR cascades. These data suggest that TrkA plays a key role in leukemogenesis and reveal an unexpected physiological role for TrkA in the pathogenesis of leukemia. These data have important implications for understanding various hematological malignancies.
authors.affiliation: Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea.
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea.
authors.forename: Gyoung Mi
authors.initials: GM
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea.
authors.forename: Yun-Jeong
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors.forename: Hye Joung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea. Electronic address: yoojink@catholic.ac.kr.
authors.forename: Yoo-Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea; Gachon Medical Research Institute, Gil Medical Center, Incheon 405-760, Republic of Korea. Electronic address: jinwo@gachon.ac.kr.
authors.forename: Wook
authors.initials: W
authors.lastname: Jin
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D049109:Cell Proliferation; D004789:Enzyme Activation; D006801:Humans; D007938:Leukemia / Q000201:enzymology* / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000473:pathology; D053858:Metabolic Networks and Pathways; D009190:Myelodysplastic Syndromes / Q000201:enzymology / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000096:biosynthesis; D019061:src-Family Kinases / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020917:Receptor, trkA; D051879:Twist-Related Protein 1; D019061:src-Family Kinases; D000097869:Polo-Like Kinase 1; C103173:TWIST1 protein, human; C000631346:CSK protein, human
keywords: Hematological malignancies; PLK-1; TrkA; Twist-1; c-Src