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.
Highlights
The Fms-like tyrosine kinase 3 (Flt3) is a type III receptor tyrosine kinase (RTK) belonging to the same subfamily as the platelet-derived growth factor (PDGF) receptors, cKit, and the macrophage colony stimulating factor (M-CSF) receptor [1]
Src-like adaptor protein (SLAP) has been shown to associate with proximal components of the T-cell receptor (TCR) and B-cell receptor (BCR) signaling complexes [16]
To determine whether SLAP interacts with receptor tyrosine kinase Flt3, we transiently expressed SLAP and Flt3 in COS-1 cells
Summary
The Fms-like tyrosine kinase 3 (Flt3) is a type III receptor tyrosine kinase (RTK) belonging to the same subfamily as the platelet-derived growth factor (PDGF) receptors, cKit, and the macrophage colony stimulating factor (M-CSF) receptor [1]. Wildtype Flt is primarily expressed in hematopoietic progenitor cells and functions in hematopoiesis. It normally promotes proliferation and differentiation of hematopoietic stem cells and progenitor cells through the activation of mitogen-activated protein kinase (MAPK) as well as phosphoinositide 3 kinase (PI3K)-Akt signaling pathways. Stimulation of Flt receptor with its ligand (FL) leads to dimerization of receptors and activation of its intrinsic tyrosine kinase activity. This event further initiates phosphorylation on tyrosine residues within the receptor intracellular domain, as well as on downstream signal transduction molecules. The phosphorylated tyrosine residues facilitate high affinity binding of signal transduction molecules containing Src homology 2 (SH2) or phosphotyrosine binding (PTB) domains
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