IndraLab

"Upon CD47 binding, SIRPA activates the phosphatase SHP-1 (ref. xref ), which inhibits the cytoskeleton-intensive phagocytosis of cells and large particles that are opsonized by antibody and complement among other antagonistic factors. xref , xref By this pathway, CD47 acts as a “Marker of Self” as originally described when CD47-deficient red cells were injected into control mice and found to be rapidly cleared by splenic macrophages. xref While marker of self capability has been examined in a variety of cell types and also synthetic beads whether such a signal would likewise function on a virus that is 100-fold smaller than a cell is unclear."

"Synaptic activation of SHP-1 phosphatase by CD47-SIRPα has been clear, but downstream targets and mechanisms in phagocytosis inhibition have remained unknown."

"In this system, SIRPα preferentially recruits and activates SHP-1 that in turn inhibits various signaling pathways particularly PI3K-Akt2, leading to dampened proinflammatory macrophage activation."

"In conclusion, these results reveal that, under proinflammatory or anti-inflammatory stimulation, SIRPα differentially binds to and activates either SHP-1 or SHP-2, leading to different signaling downstream that achieves finely tuned and distinct macrophage functions."

"Tyrosine phosphatases SHP-1 and SHP-2 are recruited and activated by ligation of SIRPα by CD47 to ITIMs, which in turn bind thrombospondin-1 (TSP-1) to CD47 on aged RBCs, thus promoting phagocytosis ([MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"Therefore, lack of SIRP-alpha expression or blockade of SIRP-alpha activity by aSIRP improved macrophage phagocytosis and suppressed production of pro-inflammatory mediators possibly through increasing STAT3 and STAT6 signaling pathways in macrophages.It was documented that SIRP-alpha activated downstream protein SHP-1 (6, 28)."

"The interaction of CD47 on he-matopoietic cells to SIRPα on macrophages is thought to prevent phagocytosis through an SIRPα-dependent activation of SHP-1 ( xref , xref , xref , xref )."

"Ligation of SIRPα with CD47 recruits and activates tyrosine phosphatases SHP-1 and SHP-2 which negatively regulate the downstream signaling pathways and effector functions ( Oldenborg, 2012 )."

"The SIRPα activation of SHP-1 determines both the life span of individual RBCs and the number of these cells in the circulation ( xref , xref , xref , xref )."

"The primary ligand for CD47 is SIRPα (also known as BIT, SHPS-1, and CD172a), which, upon binding to CD47, recruits and activates intracellular SHP1 and SHP2 proteins."

"Since Akt1 and Akt2 activities are regulated by Ser/Thr phosphorylation (Ser473/474 detected in xref ) and do not directly involve SIRPα-activated SHP-1 (a tyrosine phosphatase), we examined their upstream activator PI3K, which is regulated by tyrosine phosphorylation ( xref )."

"SIRPα preferentially recruits and activates SHP-1 under proinflammatory conditions."

"Conceptually this makes sense, given that SIRPα can signal via the cytosolic tyrosine phosphatases SHP-1 and/or SHP-2 ( Barclay and Van den Berg, 2014 )."

"It warrants us to future investigate the role of CD47 in SIRP-alpha mediated murine ALI in the future.According to the previous reports, SIRP-alpha activates downstream intracellular molecule SHP-1, leading to the suppression of macrophage activation and phagocytosis (39, 40); whereas activation of STAT3 (41, 42) and STAT6 (43, 44) signaling can promote macrophage phagocytosis."

"CD47, a ligand for signal-regulated protein-α (SIRPα) on macrophages (145), upon binding to SIRPα, SIRPα activates phosphatase-1 (SHP-1), which contains the Src homology 2 domain, to regulate intracellular signaling and inhibit cellular phagocytosis (146)."

"Although p85 bound to SHP-1 in Sirpα −/− macrophages, PI3K activity was upheld as there was no SIRPα-activated SHP-1 to dephosphorylate p85."