New Roles of Carboxypeptidase E in Endocrine and Neural Function and Cancer

Carboxypeptidase E (CPE) or carboxypeptidase H was first discovered in 1982 as an enkephalin-convertase that cleaved a C-terminal basic residue from enkephalin precursors to generate enkephalin. Since then, CPE has been shown to be a multifunctional protein that subserves many essential nonenzymatic roles in the endocrine and nervous systems. Here, we review the phylogeny, structure, and function of CPE in hormone and neuropeptide sorting and vesicle transport for secretion, alternative splicing of the CPE transcript, and single nucleotide polymorphisms in humans. With this and the analysis of mutant and knockout mice, the data collectively support important roles for CPE in the modulation of metabolic and glucose homeostasis, bone remodeling, obesity, fertility, neuroprotection, stress, sexual behavior, mood and emotional responses, learning, and memory. Recently, a splice variant form of CPE has been found to be an inducer of tumor growth and metastasis and a prognostic biomarker for metastasis in endocrine and nonendocrine tumors. (Endocrine Reviews 33: 216 -253, 2012) I. Introduction to Functions of CPE A. Discovery of CPE as a prohormone-processing enzyme B. Role of CPE in prohormone sorting, vesicle transport, and secretion C. Biomedical implications of CPE in physiological function and disease II. The CPE Gene, Biosynthesis, Protein Structure, and Distribution A. Phylogenic analysis of CPE B. Structure, biosynthesis, and intracellular trafficking of CPE C. Distribution of CPE in embryonic and adult tissues D. Biochemical and enzymatic properties of CPE III. CPE in Prohormone Sorting and Vesicle Transport A. CPE function as a prohormone sorting receptor for the regulated pathway B. CPE mediates post-Golgi hormone vesicle transport C. CPE mediates synaptic vesicle localization to nerve terminal preactive zone IV. CPE Action in the Endocrine System-Insights from Mouse Models A. Diabetes in CPE-deficient mice B. Obesity in CPE-deficient mice C. Bone metabolism in CPE-deficient mice D. Infertility and poor sexual performance in CPEdeficient mice V. CPE in Neural Function and Behavior A. Aberrant neurotransmission and dendritic architecture in CPE KO mice B. Role of CPE in stress and neuroprotection C. Regulation of mood and emotional responses in CPE mice D.