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J Biol Chem 2022 Feb 01;2982:101586. doi: 10.1016/j.jbc.2022.101586.
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Uncoupling the BMP receptor antagonist function from the WNT agonist function of R-spondin 2 using the inhibitory peptide dendrimer RWd.

Lee H , Sun R , Niehrs C .

Signaling by bone morphogenetic proteins (BMPs) plays pivotal roles in embryogenesis, adult tissue homeostasis, and disease. Recent studies revealed that the well-established WNT agonist R-spondin 2 (RSPO2) is also a BMP receptor (BMP receptor type 1A) antagonist, with roles in early Xenopus embryogenesis and human acute myeloid leukemia (AML). To uncouple the BMP antagonist function from the WNT agonist function and to promote development of AML therapeutics, here we identified a 10-mer peptide (RW) derived from the thrombospondin 1 domain of RSPO2, which specifically prevents binding between RSPO2 and BMP receptor type 1A without altering WNT signaling. We also show that a corresponding RW dendrimer (RWd) exhibiting improved half-life relieves inhibition of BMP receptor signaling by RSPO2 in human AML cells, reduces cell growth, and induces differentiation. Moreover, microinjection of RWd in Xenopus embryos ventralizes the dorsoventral embryonic patterning by upregulating BMP signaling without affecting WNT signaling. Our study corroborates the function of RSPO2 as a BMP receptor antagonist and provides a proof of concept for pharmacologically uncoupling BMP antagonist from WNT agonist functions of RSPO2 using the inhibitor peptide RWd with enhanced target selectivity and limited side effects.

PubMed ID: 35032551
Article link: J Biol Chem

Species referenced: Xenopus tropicalis
Genes referenced: acvr1 acvr2a acvr2b bmp4 bmpr1a bmpr2 crisp1.3 furin lgr4 lrp6 mapk14 rnf43 rspo2 rspo3 runx1 sdc2 smad1 szl thbs1 wnt3a znrf3
GO keywords: Wnt signaling pathway [+]
Antibodies: Ctnnb1 Ab1 MapK1 Ab5 Mapk1 Ab1 Smad1 Ab13 Smad1 Ab8 Tuba4a Ab3

Disease Ontology terms: acute myeloid leukemia
Phenotypes: Xtr Wt + RW{d} (Fig.5.C,D) [+]

Article Images: [+] show captions
References [+] :
Antebi, Combinatorial Signal Perception in the BMP Pathway. 2017, Pubmed