Although bioinformatic analysis of the increasing numbers of diverse genome sequences and amount of functional data has provided insight into the evolution of signaling networks, bioinformatics approaches have limited application for understanding the evolution of highly divergent protein families. We used biochemical analyses to determine the in vitro properties of selected divergent components of the heterotrimeric guanine nucleotide–binding protein (G protein) signaling network to investigate signaling network evolution. In animals, G proteins are activated by cell-surface seven-transmembrane (7TM) receptors, which are named G protein–coupled receptors (GPCRs) and function as guanine nucleotide exchange factors (GEFs). In contrast, the plant G protein is intrinsically active, and a 7TM protein terminates G protein activity by functioning as a guanosine triphosphatase–activating protein (GAP). We showed that ancient regulation of the G protein active state is GPCR-independent and “self-activating,” a property that is maintained in Bikonts, one of the two fundamental evolutionary clades containing eukaryotes, whereas G proteins of the other clade, the Unikonts, evolved from being GEF-independent to being GEF-dependent. Self-activating G proteins near the base of the Eukaryota are controlled by 7TM-GAPs, suggesting that the ancestral regulator of G protein activation was a GAP-functioning receptor, not a GEF-functioning GPCR. Our findings indicate that the GPCR paradigm describes a recently evolved network architecture found in a relatively small group of Eukaryota and suggest that the evolution of signaling network architecture is constrained by the availability of molecules that control the activation state of nexus proteins.

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A 35-year-old man with sickle-cell trait and diabetes who had undergone renal transplantation presented with weeks of episodic severe cramping, abdominal pain, diarrhea, maroon stool, and anorexia despite using empiric antibiotics for gastroenteritis. At presentation, his laboratory results noted a mild leukocytosis and a hemoglobin of 6.4 g/dL. Real-time polymerase chain reaction of a nasopharyngeal sample gave a positive result for SARS-CoV-2 despite the lack of respiratory symptoms or fever. A CT scan demonstrated diffusely thickening of the stomach and small-bowel walls (A). Upper endoscopy revealed normal gastric mucosa but edematous, friable duodenal mucosa with contact bleeding (B). Examination of biopsy specimens from the duodenal mucosa demonwww.giejournal.org Volume-, No.-: 2020 GASTROINTESTINAL ENDOSCOPY 1 our knowledge, this is the first endoscopic description of biopsy-confirmed COVID-19-associated microthrombosis, reinforcing the importance of endoscopy with adequate biopsy.

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