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The structural insights of stem cell factor receptor (c-Kit) interaction with tyrosine phosphatase-2 (Shp-2): An in silico analysis

Soumya Pati145, Gangenahalli U Gurudutta2, Om P Kalra3 and Asok Mukhopadhyay1*

Author Affiliations

1 Stem Cell Biology Laboratory, National Institute of Immunology, New Delhi, India

2 Stem Cell and Gene Therapy Research Lab, Institute of Nuclear Medicine and Allied Sciences, Delhi, India

3 Department of Medicine, University College of Medical Sciences & Guru Teg Bahadur Hospital, University of Delhi, New Delhi, India

4 Gene Regulation Laboratory, National Institute of Immunology, New Delhi, India

5 Current Address: Department of Neuroscience, School of Medical Sciences, University Sains Malaysia, Malaysia

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BMC Research Notes 2010, 3:14  doi:10.1186/1756-0500-3-14

Published: 22 January 2010



Stem cell factor (SCF) receptor c-Kit is recognized as a key signaling molecule, which transduces signals for the proliferation, differentiation and survival of stem cells. Binding of SCF to its receptor triggers transactivation, leading to the recruitment of kinases and phosphatases to the docking platforms of c-Kit catalytic domain. Tyrosine phosphatase-1 (Shp-1) deactivates/attenuates 'Kit' kinase activity. Whereas, Asp816Val mutation in the Kit activation loop transforms kinase domain to a constitutively activated state (switch off-to-on state), in a ligand-independent manner. This phenomenon completely abrogates negative regulation of Shp-1. To predict the possible molecular basis of interaction between c-Kit and Shp-1, we have performed an in silico protein-protein docking study between crystal structure of activated c-Kit (phosphorylated c-Kit) and full length crystal structure of Shp-2, a close structural counterpart of Shp-1.


Study revealed a stretch of conserved amino acids (Lys818 to Ser821) in the Kit activation domain, which makes decisive H-bonds with N-sh2 and phosphotyrosine binding pocket residues of the phosphatase. These H-bonds may impose an inhibitory steric hindrance to the catalytic domain of c-Kit, there by blocking further interaction of the activation loop molecules with incoming kinases. We have also predicted a phosphotyrosine binding pocket in SH2 domains of Shp-1, which is found to be predominantly closer to a catalytic groove like structure in c-Kit kinase domain.


This study predicts that crucial hydrogen bonding between N-sh2 domain of Shp-1 and Kit activation loop can modulate the negative regulation of c-Kit kinase by Shp-1. Thus, this finding is expected to play a significant role in designing suitable gain-of-function c-Kit mutants for inducing conditional proliferation of hematopoietic stem cells.