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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Nat+Commun
2017 ; 8
(1
): 477
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Engineered proteins with sensing and activating modules for automated
reprogramming of cellular functions
#MMPMID28883531
Sun J
; Lei L
; Tsai CM
; Wang Y
; Shi Y
; Ouyang M
; Lu S
; Seong J
; Kim TJ
; Wang P
; Huang M
; Xu X
; Nizet V
; Chien S
; Wang Y
Nat Commun
2017[Sep]; 8
(1
): 477
PMID28883531
show ga
Protein-based biosensors or activators have been engineered to visualize
molecular signals or manipulate cellular functions. Here we integrate these two
functionalities into one protein molecule, an integrated sensing and activating
protein (iSNAP). A prototype that can detect tyrosine phosphorylation and
immediately activate auto-inhibited Shp2 phosphatase, Shp2-iSNAP, is designed
through modular assembly. When Shp2-iSNAP is fused to the SIRP? receptor which
typically transduces anti-phagocytic signals from the 'don't eat me' CD47 ligand
through negative Shp1 signaling, the engineered macrophages not only allow
visualization of SIRP? phosphorylation upon CD47 engagement but also rewire the
CD47-SIRP? axis into the positive Shp2 signaling, which enhances phagocytosis of
opsonized tumor cells. A second SIRP? Syk-iSNAP with redesigned sensor and
activator modules can likewise rewire the CD47-SIRP? axis to the pro-phagocytic
Syk kinase activation. Thus, our approach can be extended to execute a broad
range of sensing and automated reprogramming actions for directed
therapeutics.Protein-based biosensors have been engineered to interrogate
cellular signaling and manipulate function. Here the authors demonstrate iSNAP, a
tool to detect tyrosine phosphorylation and activate desired protein enzymes
allowing the control of phagocytosis in macrophages.