Receptor Binding Proteins: the Promise of theAngiotensin type 2 (AT₂) Receptor

摘要

The purpose of this review is to document the significance of several proteins that bind with the angiotensin II type 2 receptor (AT_(2)), with emphasis on the first to be identified, the transcription factor PLZF.In this context the therapeutic potential of an AT_(2) agonist under current investigation is considered.Yeast two hybrid screening identified PLZF and two cytosolic proteins, ATIP and ATB50, as AT_(2) binding proteins.Chronic angiotensin II infusion in the AT_(2) gene deleted mouse did not result in cardiac hypertrophy.To determine the AT_(2) contribution to cardiac hypertrophy an AT_(2)signaling pathway was identified.AT_(2) activated PLZF, which translocated to the nucleus.PLZF induced the formation of p85α, the coactivator of PI3K.The downstream pathway led to enhanced protein synthesis.In addition PLZF directly induces the major cardiac transcription factor GATA4.AT_(2) and PLZF are also widely distributed in brain and function in the kidney. ATIP and ATB50 were found to be a family of ATIP isoforms, some with tumor suppressing activity.ATIP interacts with the tyrosine phosphatase SHP-1 to translocate to the nucleus and induce MMS2 a ubiquitin ligase with cellular protective effects.Phenotypes of both ATIP and SHP-1 deleted mice suggest their role as anti proliferation agents.A nonpeptide AT_(2) agonist under development, C21, shows most promise as an anti-inflammatory agent.It also holds promise for the central nervous system in stroke and in cognitive impairment.