The discovery of hidden guanylate cyclases (GCs) in the <i>Homo sapiens</i> proteome

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 <i>H. sapiens</i> 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 Mn²⁺ over Mg²⁺. 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.</p>