14-3-3 Proteins in Pineal Photoneuroendocrine Transduction: How Many Roles? D. C. Klein,  S. Ganguly,  S. L. Coon,  Q. Shi,  P. Gaildrat,  F. Morin,  J. L. Weller,  T. Obsil,y A. Hickmany and F. Dyday  Section on Neuroendocrinology, Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. yLaboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. Key words: 14-3-3, pineal, N-acetyltransferase, signal transduction, melatonin, serotonin. Abstract Recent studies suggest that a common theme links the diverse elements of pineal photoneuroendocrine transduction – regulation via binding to 14-3-3 proteins. The elements include photoreception, neurotransmission, signal transduction and the synthesis of melatonin from tryptophan. We review general aspects of 14-3-3 proteins and their biological function as binding partners, and also focus on their roles in pineal photoneuroendocrine transduction. The function of the pineal gland as a photoneuroendocrine transducer involves multiple processes, including photoreception, signal transduction and the synthesis of melatonin from trypto- phan. In addition, in birds and mammals, adrenergic neurotrans- mission plays a regulatory role. Recent studies suggest that a common theme links these diverse processes, one that has been generally ignored: regulation via binding to 14-3-3 proteins. We review general aspects of 14-3-3 proteins, their biological role as binding partners and their roles in pineal photoneuroendocrine transduction. 14-3-3 proteins: background and biological role as binding partners 14-3-3 proteins are widely distributed in biology (1–5). They were discovered during an effort to characterize brain proteins, which revealed the presence of a relatively abundant group of acidic proteins. The name 14-3-3 reflects their behaviour in DEAE- cellulose chromatography and starch gel electrophoresis (6). The 14-3-3 family of proteins is comprised of homologous 30 and 33 kDa isoforms that typically occur in cells as soluble hetero- and homodimers. There are seven known mammalian 14-3-3 isoforms, designated b, e, g, Z, s, t and z, according to their elution pattern in reverse phase column chromatography. In addition, the phosphorylated forms of the b and z isoforms, have been identified as a and d isoforms, respectively (1–4). There is little known about what controls the relative abundance of each isoform in a particular cell, whether the abundance of any one isoform can be selectively controlled or if 14-3-3 proteins are constitutively expressed as house-keeping genes. 14-3-3 proteins are most abundant in the cytoplasm, although it is clear they can be associated with proteins lodged in membranes. In addition, they occur in the nucleus, reflecting their role in the shuttling of some transcription factors across the nuclear mem- brane (1–4). All actions of 14-3-3 proteins involve binding to target proteins, over 100 of which have been identified; there is little doubt that this number will increase many-fold as a result of the current interest in functional proteomics and protein–protein interactions. Review of the known 14-3-3 binding partners reveals that they have little in common on a functional or structural basis, other than the capacity to bind to 14-3-3 proteins. Of special interest to students of pineal photoneuroendocrine transduction is that the first functionally important role established for any 14-3-3 protein was that of an activator of tryptophan and tyrosine hydroxylases (7). In many cases, binding is controlled by serine/threonine phosphorylation of these target proteins. That is, phosphorylation of the target proteins switches them from nonbinding to high affinity binding partners. Through this phosphorylation-dependent binding mechanism, 14-3-3 proteins are critical elements of signal transduction and are involved in a broad range of functions, including actions on cell cycle, apoptosis, protein trafficking, enzyme activation/protection, mitogenic signal transduction, transmitter release, catecholamine and serotonin synthesis, recep- tor function, ion channel activity and, of special relevance to pineal function, the conversion of serotonin to melatonin (1–4). Journal of Neuroendocrinology, 2003, Vol. 15, 370–377 # 2003 Blackwell Publishing Ltd Correspondence to: Dr David C. Klein, NIH 49/6A82, Bethesda, MD 20892-4480, USA (e-mail: klein@helix.nih.gov).