Cytokine receptor-like factor 3 (CRLF3) (CRLF3)

Cytokine receptor-like factor 3 (CRLF3) is a highly conserved type I cytokine receptor that was initially characterized as an unknown cytokine receptor-like molecule (p48.2) due to its unique intracellular localization and structural features, including a fibronectin type III domain and a WSXWS-like motif. It plays a critical role in regulating the cell cycle, specifically inducing G0/G1 arrest, and is frequently deleted in patients with neurofibromatosis type 1 (NF1) microdeletion syndrome. Recent research has identified CRLF3 as a key regulator of the final stage of platelet production (thrombopoiesis), where it controls the fission of preplatelets into mature platelets by modulating microtubule stability through interactions with the Hippo pathway. This makes CRLF3 a promising therapeutic target for essential thrombocythemia, as its deficiency or inhibition can specifically normalize platelet counts without affecting other blood lineages. Additionally, CRLF3 serves as a neuroprotective receptor for erythropoietin (Epo) and its variants, mediating survival signals in neurons via the JAK/STAT pathway, which suggests potential applications in treating neurodegenerative conditions.

Other names

p48.2CREME9CYTOR4Cytokine receptor-related protein 4Type I cytokine receptor-like factor p48

Agonism of CRLF3 by erythropoietin or its variants activates JAK/STAT signaling for neuroprotection; inhibition of CRLF3 is a proposed mechanism to reduce platelet overproduction in essential thrombocythemia by preventing preplatelet fission.