Abstract
Signal regulatory protein (SIRP)-α1 is a myeloid inhibitory immunoreceptor. SIRPα1 expression is significantly reduced in the majority of myeloid malignancies. SIRPα1 is a negative regulator of signaling and the reduced expression is considered to play a role in the pathogenesis of these diseases through aberrant signaling, but the biological roles of SIRPα1 remain largely unknown. In this study, by using SIRP-α1-knockdown chronic myeloid leukemia K562 (K562SIRP-α1KD) cells, I found that in low (0.1, 0.3%) serum media, the cell growth was increased until day 5, whereas control cells did not proliferate beyond day 2 under the same serum conditions. Consistently, in K562SIRP-α1KD cells, 2 days of culture in 0.3% serum increased the proportion of S-phase cells, as well as bromodeoxyuridine (BrdU) incorporation compared to their controls. Moreover, serum stimulation experiment revealed that Brd-U positive cells were significantly increased in K562SIRPα1 KD cells. Furthermore, in K562SIRP-α1KD cells, phosphorylation of extracellular regulated kinase (ERK) and Akt was potently increased under low serum conditions. Collectively, these data suggested that down-regulation of SIRPα1 led to the constitutive activation of these aberrant signaling, as well as abnormal growth, in K562 cells.
Highlights
The signal regulatory protein (SIRP) α1, termed CD172a or Src homology 2 domain-containing phosphatase substrate-1 (SHPS-1), is a cell surface receptor expressed predominantly in monocytes, granulocytes, dendritic cells, as well as hematopoietic stem cells [1, 11, 25]
We revealed that downregulation of SIRPα1 results in the aberrant phosphorylation of several signaling pathway components, such as extracellular regulated kinase (ERK), Akt and glycogen synthase kinase (GSK)-3β, which may lead to the induction of β-catenin
The cell growth was increased until day 5 in K562SIRPα1KD cells, whereas control cells did not proliferate beyond day 2 under the same serum conditions (Figure 1)
Summary
The signal regulatory protein (SIRP) α1, termed CD172a or Src homology 2 domain-containing phosphatase substrate-1 (SHPS-1), is a cell surface receptor expressed predominantly in monocytes, granulocytes, dendritic cells, as well as hematopoietic stem cells [1, 11, 25]. Its overexpression leads to a reduced responsiveness to tyrosine kinase ligands, such as epidermal growth factor, platelet-derived growth factor and insulin [11]. These suggest that, SIRPα1 is considered as a negative regulator of signaling. The reduced expression is considered to play a role in the pathogenesis of these diseases through aberrant signaling, such as SHP-1 and its downstream signaling KIT pathway [26]
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