Abstract
During last decade or more, investigations have been pursued towards finding molecular cross-talks involving proto-oncogene transformation to oncogene in aggressive form of hematological malignancies. Oncologists and structural biologists have identified several hotspots in tyrosine kinase proto-oncogenes, which decided the diverse aberrant cell fate decisions in cancers. But direct exploitation of the aberrant behavior of tyrosine kinase oncogenes in regenerative cell therapies has not been thought, so far. The present report has introduced a novel outlook for hematopoietic stem cells (HSCs) therapy on the basis of structural and functional interpretation of stem cell factor receptor (c-Kit), which can change the perspectives of oncogene-oriented structural biology approach. c-Kit, the master signal transducer of HSCs holds many structural intricacies, for which it becomes vulnerable to the extent of oncogenic activation or inactivation. Both these attributes strictly involve in deciding on the fate of HSCs signaling. c-Kit hyperactivity contributes to oncogenic signaling of HSCs, leading to hematological malignancies. Whereas, c-Kit inactivation leads to irreversible developmental defects. Conserved hotspots in c-Kit structure have long been discussed by cell biologists as well as structural biologists, as these sites delineate the sensitivity towards kinase inhibitors or anticancer drugs. Recent studies of our group envisaged a new dimension to c-Kit’s interaction with one of its negative regulators. The study suggested crucial hydrogen bonds between c-Kit catalytic domain and tyrosine phosphatase-1 (SHP-1) regulate its kinase activity. So, disruption of any such bonding between c-Kit and its negative regulator may lead to hyperactive variants. Study also suggested an interesting hypothesis, which explains transient ectopic expression of hyper-activating Kit-mutant can induce early commitment of hematopoiesis in lethally irradiated mice. We have hypothesized that designing non-oncogenic or partial hyper-activating mutants in c-Kit may generate new class of active variants. This approach may lead to the generation of therapeutic candidates for HSCs specific molecular targets in regenerative medicine using other existing proto-oncogenes.
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Pati, S., Mukhopadhyay, A. (2012). Recovery of the Bone Marrow in Lethally Irradiated Host: Role of Hyper-Activated Stem Cell Factor Receptor. In: Hayat, M. (eds) Stem Cells and Cancer Stem Cells, Volume 7. Stem Cells and Cancer Stem Cells, vol 7. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4285-7_8
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