The ability to selectively bind diverse substances and convert the binding events into amplifiable, transmissible and measurable chemical queues is the fundamental basis of biological signaling. Artificially designed synthetic orthorgonal sensing and signal transduction cascades (i.e occurring in parallel to natural pathways, but not using overlapping nodes) would enable us to elucidate the fundamental principles of signal propagation in biological systems both in vitro and in vivo. They also will allow us to re-design living organisms at all levels of complexity and create a range of new biotechnological applications. Here we set to achieve this goal by creating a series of auto-inhibited proteases with non-overlapping substrate specificities that can be arranged in artificial signal amplification cascades of various architectures. Such proteases can be activated by either proteolytic cleavage of the inhibitor, or by a conformational change that dislodges the inhibitor from the active site of the protease. The latter feature is be used to create receptors by incorporating a binding domain that undergoes conformational changes upon ligand binding between protease and its inhibitor.  We demonstrate that developed synthetic sensors can detect protease activates and specific peptides in complex biological samples. We expect that this approach will lead to design of a large array of synthetic allosteric receptors and signal transduction pathways. The biotechnological implications of this development will be discussed.