The discovery of hidden guanylate cyclases (GCs) in the Homo sapiens proteome

Recent discoveries have established functional guanylate cyclase (GC) catalytic centers with low activity within kinase domains in plants. These crypto GCs generate guanosine 3’,5’-cyclic monophosphate (cGMP) essential for both intramolecular and downstream signaling. Here, we have set out to search for such crypto GCs moonlighting in kinases in the H. sapiens proteome and identified 18 candidates, including the neurotropic receptor tyrosine kinase 1 (NTRK1). NTRK1 shows a domain architecture much like plant receptor kinases such as the phytosulfokine receptor, where a functional GC essential for downstream signaling is embedded within a kinase domain. In vitro characterization of the NTRK1 shows that the embedded NTRK1 GC is functional with a marked preference for Mn(2+) over Mg(2+). This therefore points to hitherto unsuspected roles of cGMP in intramolecular and downstream signaling of NTRK1 and the role of cGMP in NTRK1-dependent growth and neoplasia.