Structural and functional analysis of KIT gene encoding receptor tyrosine kinase and its interaction with sunitinib and HDAC inhibitors: an in silico approach.

@article{Vanajothi2012StructuralAF,
  title={Structural and functional analysis of KIT gene encoding receptor tyrosine kinase and its interaction with sunitinib and HDAC inhibitors: an in silico approach.},
  author={Ramar Vanajothi and Sundararaj Rajamanikandan and Arumugam Sudha and Pappu Srinivasan},
  journal={Pakistan journal of biological sciences : PJBS},
  year={2012},
  volume={15 3},
  pages={
          121-31
        }
}
KIT is a growth factor receptor, important for normal germ cell migration and development. The malfunction of KIT gene results in constitutive activation of the tyrosine kinase activity of c-KIT which is believed to be the major oncogenic event in stomach, small intestine mastocytosis, acute leukemias, melanomas and colon tumors. The genetics of these diseases could be better understood by knowing the functional relevance of their SNP variation. In this study, a computational analysis to detect… 
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Prediction of the Damage-Associated Non-Synonymous Single Nucleotide Polymorphisms in the Human MC1R Gene
TLDR
The computational analysis proved capable of identifying the potentially damaging nsSNPs in MC1R, which are candidates for further laboratory studies of the functional and pharmacological significance of the alterations in the receptor and the phenotypic outcomes.
Computational characterization of deleterious SNPs in Toll-like receptor gene that potentially cause mastitis in dairy cattle
TLDR
Results obtained from various tools used in the study shows that the deleterious non-synonymous SNPs of TLR2 may responsible for the mutation of Arginine to Histidine at 563 and Threonine to Methionine at 605 and exhibit greatest impact on protein stability.
Predicting the effect of non synonymous SNPs in bovine TLR4 gene
TLDR
The computational analysis proved capable of identifying the potentially damaging nsSNPs in TLR4, which are candidates for further laboratory studies of the functional significance of the alterations in the receptor and the phenotypic outcomes.
Computational analysis of non-synonymous SNPs in bovine Mx1 gene
TLDR
The results of computational analysis of the Mx1 gene further widens the scope of research on mutations that can be prioritized in future population and laboratory studies.

References

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The D816V Mutation of c-Kit Circumvents a Requirement for Src Family Kinases in c-Kit Signal Transduction*
TLDR
It is demonstrated that the signal transduction pathways mediated by c-Kit/D816V are markedly different from those activated by wild-type c- Kit and that altered substrate specificity ofc-Kit circumvents a need for Src family kinases in signaling of growth and survival, thereby contributing to the transforming potential of c-kit/D 816V.
Inhibitors of deacetylases suppress oncogenic KIT signaling, acetylate HSP90, and induce apoptosis in gastrointestinal stromal tumors.
TLDR
Results provide preclinical evidence for a disease-specific effect of HDACI in KIT-positive GIST, which could translate into therapeutic activity.
In silico analysis of structural and functional consequences in p16INK4A by deleterious nsSNPs associated CDKN2A gene in malignant melanoma.
TLDR
It is proposed that the SNP with the ID rs11552822 could be the most deleterious nsSNP in CDKN2A gene, causing malignant melanoma, as it was well correlated with experimental studies carried out elsewhere.
Structure of a c-Kit Product Complex Reveals the Basis for Kinase Transactivation*
TLDR
The results provide key insights into the molecular basis for c-Kit kinase transactivation to assist in the design of new competitive inhibitors targeting activated mutant forms of c- Kit that are resistant to current chemotherapy regimes.
KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors.
TLDR
Findings indicate that KIT may be activated by mutations in at least three domains-extracellular, juxtamembrane, and kinase-in GISTs.
Effect of deleterious nsSNP on the HER2 receptor based on stability and binding affinity with herceptin: a computational approach.
TLDR
It is proposed that SNPid rs4252633 could be the most deleterious nsSNP for HER2 receptor, and that herceptin could beThe best drug for mutant compared to the native HER2 target.
Structural Basis for the Autoinhibition and STI-571 Inhibition of c-Kit Tyrosine Kinase*
TLDR
The 1.9-Å resolution crystal structure of native c-Kit kinase in an autoinhibited conformation is reported and will facilitate the structure-guided design of specific inhibitors that target the activated andAutoinhibited conformations of c- Kit kinase.
Mutations in Exon 11 of the c-kit Gene in a Myogenic Tumor and a Neurogenic Tumor as Well as in Gastrointestinal Stromal Tumors
TLDR
It is concluded that the gain-of-function mutation in exon 11 of the c-kit gene is an important prognostic factor for gastrointestinal mesenchymal tumors, including myogenic and neurogenic tumors as well as GISTs.
The role of KIT in the management of patients with gastrointestinal stromal tumors.
TLDR
It is becoming evident that alternative approaches to direct KIT inhibition will be required for long-term survival of patients with advanced GISTs, and Sunitinib has recently been approved for patients with GIST; and additional small molecule inhibitors are in the pipeline.
Signalling by the W/Kit receptor tyrosine kinase is negatively regulated in vivo by the protein tyrosine phosphatase Shp1
TLDR
DNA analysis in mammals shows that homozygosity for mutations in both W and me ameliorates aspects of both the me and W phenotypes, demonstrating that the Kit receptor plays a role in the pathology of the me phenotype and conversely that Shp1 negatively regulates Kit signalling in vivo.
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