Please use this identifier to cite or link to this item: https://doi.org/10.1182/blood-2011-10-388611
Title: Adaptor protein Lnk binds to and inhibits normal and leukemic FLT3
Authors: Lin, D.-C.
Yin, T.
Koren-Michowitz, M.
Ding, L.-W. 
Gueller, S.
Gery, S.
Tabayashi, T.
Bergholz, U.
Kazi, J.U.
Rönnstrand, L.
Stocking, C.
Koeffler, H.P.
Issue Date: 18-Oct-2012
Source: Lin, D.-C., Yin, T., Koren-Michowitz, M., Ding, L.-W., Gueller, S., Gery, S., Tabayashi, T., Bergholz, U., Kazi, J.U., Rönnstrand, L., Stocking, C., Koeffler, H.P. (2012-10-18). Adaptor protein Lnk binds to and inhibits normal and leukemic FLT3. Blood 120 (16) : 3310-3317. ScholarBank@NUS Repository. https://doi.org/10.1182/blood-2011-10-388611
Abstract: Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase with important roles in hematopoietic progenitor cell survival and proliferation. It is mutated in approximately one-third of AML patients, mostly by internal tandem duplications (ITDs). Adaptor protein Lnk is a negative regulator of hematopoietic cytokine signaling. In the present study, we show that Lnk interacts physically with both wildtype FLT3 (FLT3-WT) and FLT3-ITD through the SH2 domains. We have identified the tyrosine residues 572, 591, and 919 of FLT3 as phosphorylation sites involved in direct binding to Lnk. Lnk itself was tyrosine phosphorylated by both FLT3 ligand (FL)-activated FLT3-WT and constitutively activated FLT3-ITD. Both shRNA-mediated depletion and forced overexpression of Lnk demonstrated that activation signals emanating from both forms of FLT3 are under negative regulation by Lnk. Moreover, Lnk inhibited 32D cell proliferation driven by different FLT3 variants. Analysis of primary BM cells from Lnk-knockout mice showed that Lnk suppresses the expansion of FLstimulated hematopoietic progenitors, including lymphoid-primed multipotent progenitors. The results of the present study show that through direct binding to FLT3, Lnk suppresses FLT3-WT/ITD-dependent signaling pathways involved in the proliferation of hematopoietic cells. Therefore, modulation of Lnk expression levels may provide a unique therapeutic approach for FLT3-ITD-associated hematopoietic disease. © 2012 by The American Society of Hematology.
Source Title: Blood
URI: http://scholarbank.nus.edu.sg/handle/10635/116917
ISSN: 00064971
DOI: 10.1182/blood-2011-10-388611
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
There are no files associated with this item.

SCOPUSTM   
Citations

27
checked on Mar 14, 2018

WEB OF SCIENCETM
Citations

22
checked on Mar 14, 2018

Page view(s)

26
checked on Mar 11, 2018

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.