Src-Like Adaptor Protein (SLAP) Binds to the Receptor Tyrosine Kinase Flt3 and Modulates Receptor Stability and Downstream Signaling
Open Access
- 31 December 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (12), e53509
- https://doi.org/10.1371/journal.pone.0053509
Abstract
Fms-like tyrosine kinase 3 (Flt3) is an important growth factor receptor in hematopoiesis. Gain-of-function mutations of the receptor contribute to the transformation of acute myeloid leukemia (AML). Src-like adaptor protein (SLAP) is an interaction partner of the E3 ubiquitin ligase Cbl that can regulate receptor tyrosine kinases-mediated signal transduction. In this study, we analyzed the role of SLAP in signal transduction downstream of the type III receptor tyrosine kinase Flt3. The results show that upon ligand stimulation SLAP stably associates with Flt3 through multiple phosphotyrosine residues in Flt3. SLAP constitutively interacts with oncogenic Flt3-ITD and co-localizes with Flt3 near the cell membrane. This association initiates Cbl-dependent receptor ubiquitination and degradation. Depletion of SLAP expression by shRNA in Flt3-transfected Ba/F3 cells resulted in a weaker activation of FL-induced PI3K-Akt and MAPK signaling. Meta-analysis of microarray data from patient samples suggests that SLAP mRNA is differentially expressed in different cancers and its expression was significantly increased in patients carrying the Flt3-ITD mutation. Thus, our data suggest a novel role of SLAP in different cancers and in modulation of receptor tyrosine kinase signaling apart from its conventional role in regulation of receptor stability.Keywords
This publication has 28 references indexed in Scilit:
- The Src-Like Adaptor Protein Regulates GM-CSFR Signaling and Monocytic Dendritic Cell MaturationThe Journal of Immunology, 2011
- CBL Exon 8/9 Mutants Activate the FLT3 Pathway and Cluster in Core Binding Factor/11q Deletion Acute Myeloid Leukemia/Myelodysplastic Syndrome SubtypesClinical Cancer Research, 2009
- The Src-like adaptor protein regulates PDGF-induced actin dorsal ruffles in a c-Cbl-dependent mannerOncogene, 2008
- Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent mannerProceedings of the National Academy of Sciences of the United States of America, 2006
- Src-like adaptor protein regulates TCR expression on thymocytes by linking the ubiquitin ligase c-Cbl to the TCR complexNature Immunology, 2005
- Gene expression profiling of acute promyelocytic leukaemia identifies two subtypes mainly associated with Flt3 mutational statusLeukemia, 2005
- Src-like adaptor protein down-regulates T cell receptor (TCR)–CD3 expression by targeting TCRζ for degradationThe Journal of cell biology, 2005
- Reliability analysis of microarray data using fuzzy c-means and normal mixture modeling based classification methodsBioinformatics, 2004
- Up-regulation of SLAP in FLI-1-transformed erythroblasts interferes with EpoR signalingBlood, 2003
- FLT3: ITDoes matter in leukemiaLeukemia, 2003