title: Cathepsin S signals via PAR2 and generates a novel tethered ligand receptor agonist.
abstract: Protease-activated receptor-2 is widely expressed in mammalian epithelial, immune and neural tissues. Cleavage of PAR2 by serine proteases leads to self-activation of the receptor by the tethered ligand SLIGRL. The contribution of other classes of proteases to PAR activation has not been studied in detail. Cathepsin S is a widely expressed cysteine protease that is upregulated in inflammatory conditions. It has been suggested that cathepsin S activates PAR2. However, cathepsin S activation of PAR2 has not been demonstrated directly nor has the potential mechanism of activation been identified. We show that cathepsin S cleaves near the N-terminus of PAR2 to expose a novel tethered ligand, KVDGTS. The hexapeptide KVDGTS generates downstream signaling events specific to PAR2 but is weaker than SLIGRL. Mutation of the cathepsin S cleavage site prevents receptor activation by the protease while KVDGTS retains activity. In conclusion, the range of actions previously ascribed to cysteine cathepsins in general, and cathepsin S in particular, should be expanded to include molecular signaling. Such signaling may link together observations that had been attributed previously to PAR2 or cathepsin S individually. These interactions may contribute to inflammation.
authors: Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Sarina B
authors: SB
authors: Elmariah
authors: Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Vemuri B
authors: VB
authors: Reddy
authors: Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Ethan A
authors: EA
authors: Lerner
mesh_terms: D000595:Amino Acid Sequence; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D025941:Protein Interaction Mapping; D044464:Receptor, PAR-2 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D044464:Receptor, PAR-2; D002403:Cathepsins; C028217:cathepsin S