Cytokine receptor-like factor 3 (CRLF3) is an phylogenetically ancient class 1 cytokine receptor present in all major eumetazoan taxa ranging from cnidarians to mammals. In humans, CRLF3 is expressed in various tissues and has been associated with proliferation, differentiation, cell survival and some diseases. Our studies on insect neurons and human iPSC-derived neurons demonstrated that CRLF3 (whose insect-endogenous ligand is still unidentified) can be activated by human erythropoietin (EPO) and its non-erythropoietic splice variant EV-3. Under apoptogenic conditions, CRLF3 initiates pro-survival mechanisms mediated through regulation of pro- and antiapoptotic genes. In insects, these mechanisms include the prevention of elevated acetylcholinesterase levels, which acts as a major driver of apoptosis in both insect and mammalian cells. Hence, frequently reported Epo-mediated neuroprotection in mammals may partly result from activation of CRLF3 in addition to the specific EpoReceptor. We hypothesize that receptors for specific vertebrate cytokines (Epo, EV-3, thrombopoietin, growth hormone, prolactin etc.) evolved from CRLF3, while these cytokines retained the ability to activate general cell-protection via CRLF3. We have confirmed interaction with insect CRLF3 for Epo, EV-3 and thrombopoietin and are currently testing GSF, GC-SF, prolactin and growth hormone for similar effects. We compare the ligand binding spectrum of insect CRLF3 with its human homolog in SH-SY5Y neuroblastoma cells. We use survival assays with rotenone-treated SH-SY5Y neuroblastoma cell lines to explore cytokine effects on cell survival and expression of pro- and anti-apoptotic factors including acetylcholinesterase.