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Abstract

Receptor tyrosine kinases (RTKs) are key regulators of cellular functions in metazoans. In vertebrates, RTKs are mostly activated by polypeptides but are not naturally sensitive to amino acids or light. Taking inspiration from Venus Kinase Receptors (VKRs), an atypical family of RTKs found in Nature, we have achieved the transformation of the human insulin (hIR) and hepatocyte growth factor receptor (hMET) into glutamate receptors by replacing their extracellular binding domains with the ligand‐binding domain of metabotropic glutamate receptor type 2 (mGluR2). We then imparted light sensitivity by covalent attachment of a synthetic, glutamate‐based photoswitch onto a self‐labelling SNAP tag. Employing a Xenopus laevis oocyte kinase activity assay, we demonstrate how these chimeric RTKs, termed LihIR (Light‐controlled human Insulin Receptor) and LihMET (Light‐controlled human MET Receptor), can be used to exert optical control over insulin or MET signaling pathways. Our results outline a potentially general strategy to convert RTKs into photoreceptors.