LAUSR

ABSTRACT The biological mechanisms underlying the effects of stem cell factor (SCF) and an inhibitor, NSC87877 (N) of the c‐Kit negative regulator (SHP‐1 and SHP‐2) on cell proliferation are different. Therefore, we compared the cell's response to these two either alone or in combination in K562 cells. Binding of SCF (S) to c‐Kit induces dimerization that activates its kinase activity. The activated c‐Kit undergoes autophosphorylation at tyrosine residues that serve as a docking site for signal transduction molecules containing SH2 domains. Predominantly, the phosphotyrosine 568 (pY568) in Juxtamembrane (JM) region of c‐Kit interacts with adaptor protein APS, Src family kinase, and SHP‐2, while phosphotyrosine 570 (pY570) interacts with the SHP‐1 and the adaptor protein Shc. The dephosphorylation of phosphotyrosine residues by SHP‐1/SHP‐2 leads to inhibition of c‐Kit proliferative signaling. A chemical molecule, N is reported to inhibit the enzymatic activity of SHP‐1/SHP‐2, but its effect on c‐Kit‐mediated proliferation has not been studied yet. Thus, this work aims at examining the effect of the combination of S and N on cells growth as compared to individual treatment. The present study is performed with erythroleukemic K562 cells, chosen for its mRNA expression concerning the c‐Kit, and SHP‐1/SHP‐2. Interestingly, proliferation assay showed that combination significantly increased proliferation when G1 sorted K562 cells were used. These changes were significantly higher when K562 cells were initially treated with N followed by S treatment. Collectively, these results give mechanistic insight into the proliferation enhancement of bone marrow transplantation through the synergistic effect of S and N by inhibiting SHP‐1/SHP‐2. The study gives solid evidence that S and N combination can be used to enhance cell proliferation/growth.