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Fig. 8 Schema of Rnf111 regulating the development of hematopoietic stem and progenitor cells by maintaining Smad2/3 phosphorylation and activating the Gcsfr/NO signaling pathway. Left. At a physiological concentration of transforming growth factor-beta (TGF-β), ARK/Rnf111 maintains Smad2/3 phosphorylation by promoting the degradation of Smad7 and further facilitates activation of the Gcsfr/NO signaling pathway to ensure the proliferative response of HSPC to TGF-β. Right. Deletion of ARK/Rnf111 in hematopoietic stem and progenitor cells (HSPC) leads to a weakening of TGF-β signaling output, which is manifested by a decrease in the Gcsfr/NO signal, resulting in an attenuated proliferative response of HSPC to TGF-β.