c-Src activation through a TrkA and c-Src interaction is essential for cell proliferation and hematological malignancies

Biochem Biophys Res Commun. 2013 Nov 15;441(2):431-7. doi: 10.1016/j.bbrc.2013.10.082. Epub 2013 Oct 26.

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.

Keywords: Hematological malignancies; PLK-1; TrkA; Twist-1; c-Src.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CSK Tyrosine-Protein Kinase
  • Cell Cycle Proteins / biosynthesis
  • Cell Proliferation
  • Enzyme Activation
  • Humans
  • Leukemia / enzymology*
  • Leukemia / pathology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / pathology
  • Metabolic Networks and Pathways
  • Myelodysplastic Syndromes / enzymology
  • Myelodysplastic Syndromes / pathology
  • Nuclear Proteins / biosynthesis
  • Polo-Like Kinase 1
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein Serine-Threonine Kinases / biosynthesis
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, trkA / metabolism*
  • Tumor Cells, Cultured
  • Twist-Related Protein 1 / biosynthesis
  • src-Family Kinases / metabolism*

Substances

  • Cell Cycle Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • TWIST1 protein, human
  • Twist-Related Protein 1
  • Receptor, trkA
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt