Rational design of heterodimeric receptors capable of activating target signaling molecules

Kongkrongtong, Tatphon; Zhang, Ruolan; Kawahara, Masahiro

doi:10.1038/s41598-021-96396-3

Cited by 2 publications

(2 citation statements)

References 25 publications

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“…2 c). The result is consistent with our recent study showing that STAT3 or STAT5, but not STAT1, promotes proliferation of Ba/F3 cells 25 , 26 . These results indicate that the engineered receptor scaffold activates signaling molecules bound to the tyrosine motif in response to the synthetic ligand AP20187.…”

Section: Resultssupporting

confidence: 94%

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Phenotypic screening of signaling motifs that efficiently induce cell proliferation

Umene,

Nagamune,

Kawahara

2023

Sci Rep

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Since cell proliferation is one of the fundamental cell fates, artificial control of cell proliferation based on a receptor-engineering approach is increasingly important in therapeutic and industrial applications. Since the signal transduction properties of cytokine receptors are greatly influenced by the amino acid sequence of tyrosine motifs, here we develop a phenotypic screening approach that can directly select cell proliferation-inducing tyrosine motifs from a synthetic library. In the tyrosine motif library, amino acid sequences around the tyrosine are randomized to attain diverse binding patterns of signaling molecules. Theoretically, engineered receptors with distinct tyrosine motifs would activate signaling molecules in diverse patterns. Thus, we investigated whether tyrosine motif sequences capable of inducing cell proliferation could be selected from the cellular library expressing the motif-engineered receptors. Consequently, the selected motifs induced similar levels of cell proliferation compared to the cytoplasmic signaling domain of a native receptor. The motif-screening system was applicable to cells that may differentiate or proliferate depending on cytokine signals. To our best knowledge, this is the first report demonstrating phenotypic screening of tyrosine motifs in living cells. Our approach would open up new possibilities in the field of artificial control of cell fate based on signal transduction engineering.

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Section: Resultssupporting

confidence: 94%

“…The signaling analyses of the selected tyrosine motif clones demonstrated that proliferation-inducing signaling molecules such as STAT5, MEK, and Akt were activated in both Ba/F3 and 32Dcl3 cells. As shown in our previous study, proliferation of Ba/F3 cells is promoted by STAT3 or STAT5 25 , 26 . The introductory experiments (Fig.…”

Section: Discussionsupporting

confidence: 63%

Phenotypic screening of signaling motifs that efficiently induce cell proliferation

Umene,

Nagamune,

Kawahara

2023

Sci Rep

Self Cite

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Synthetic receptor scaffolds significantly affect the efficiency of cell fate signals

Umene,

Kawahara

2024

Sci Rep

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Mimicry of receptor functions by designing synthetic receptors would be one of the recently hot research trends in cell engineering. While several types of synthetic receptors have been designed to induce desired cell fates in response to external stimuli, little is known about which receptor type signals more efficiently for inducing a certain cell fate. In this study, we compared the performance of three types of synthetic receptor scaffolds, i.e. myristoylated, cytosolic, and transmembrane types that signal through JAK-dependent phosphorylation of tyrosine motifs to transduce growth signaling. As a result, the phosphorylation levels of JAK and subsequent downstream signaling molecules were significantly maintained in the cytosolic type receptors, leading to more efficient cell growth than the other types. In contrast, the phosphorylation levels of JAK decreased in a motif-dependent manner in the transmembrane type receptors. Although various studies on receptor engineering based on domain or motif engineering have been reported, to our knowledge this study is the first to demonstrate that synthetic receptor scaffolds significantly affect the efficiency of cell fate signals. These findings are important for both receptor biology and receptor engineering, providing guidelines for rationally designing synthetic receptors that can transduce as efficient signaling as possible.

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Rational design of heterodimeric receptors capable of activating target signaling molecules

Cited by 2 publications

References 25 publications

Phenotypic screening of signaling motifs that efficiently induce cell proliferation

Phenotypic screening of signaling motifs that efficiently induce cell proliferation

Synthetic receptor scaffolds significantly affect the efficiency of cell fate signals

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