Lee WY, Wang CJ, Lin TY, Hsiao CL, Luo CW. CXCL17, an orphan chemokine, acts as a novel angiogenic and anti-inflammatory factor. Am J Physiol Endocrinol Metab 304: E32-E40, 2013. First published October 31, 2012; doi:10.1152/ajpendo.00083.2012.-Chemokines play pivotal roles in the recruitment of various immune cells to diverse tissues in both physiological and pathological conditions. CXCL17 is an orphan chemokine preliminarily found to be involved in tumor angiogenesis. However, its protein nature, as well as its endogenous bioactivity, has not been well clarified. Using real-time PCR, immunohistochemical staining, and Western blotting, we found that CXCL17 is highly expressed in both a constitutive and inducible manner in the rat gastric mucosa, where it undergoes endoproteolysis during protein maturation. The mature CXCL17 exhibited strong chemoattractant abilities targeting monocytes and macrophages, potentially through ERK1/2 and p38 but not JNK signaling. CXCL17 also induced the production of proangiogenic factors such as vascular endothelial growth factor A from treated monocytes. Furthermore, in contrast to other CXC chemokines that accelerate inflammatory responses, CXCL17 showed novel anti-inflammatory effects on LPS-activated macrophages. Therefore, our data suggest that CXCL17 in the gastric lamina propria may play an important role in tissue repair and anti-inflammation, both of which help to maintain the integrity of the gastric mucosa. endoproteolysis; macrophages; stomach CHEMOKINES ARE A GROUP OF CHEMOTACTIC CYTOKINES that govern the recruitment of various leukocytes to inflammation sites. In addition to promoting the trafficking of leukocytes, recent studies indicate that chemokines also play important roles in many aspects, including tumor growth, angiogenesis, organ sclerosis, and autoimmunity (21). Based on sequence homology and the numbers of amino acids between the first two cysteines, chemokines can be subdivided into C, CC, CXC, and CX 3 C subgroups (15). Chemokines bind to G protein-coupled receptors (GPCRs) on different target cells to initiate intracellular signaling cascades. Although the physiological roles and cognate receptors of most chemokines have been well characterized (34), the endogenous function as well as the receptor nature of CXCL17, the most recent chemokine ligand to be reported (17), are still unclear.CXCL17 was originally identified in 2006 by threading methods as having a protein structure similar to the CXC chemokine family (17). Although its physiological functions have not been clearly explored, two studies have proposed that CXCL17 might act as a chemokine that accelerates tumor progression (13,30). Overexpression of CXCL17 in NIH3T3 or hepatocellular carcinoma cells significantly promotes their tumor formation capability in nude mice. Microarray analyses have indicated that the CXCL17 transcript is elevated dramatically in breast and colon tumors, where its level is tightly coregulated in concert with vascular endothelial growth factor (VEGF) expression. Becau...

Mutation in either of the genes encoding bone morphogenetic protein (BMP) 8A or 8B ( or ) causes postnatal depletion of spermatogonia in mice. We found that, but not , was expressed predominantly in the neonatal mouse spermatogonia. Although most BMPs induce activation of SMADs 1, 5, and 8 (SMAD1/5/8), but not SMADs 2 and 3 (SMAD2/3), we found that BMP8A induced signaling through both sets of transcription factors. In undifferentiated mouse spermatogonia, BMP8A activated SMAD1/5/8 through receptor complexes formed by ALK3 and either ACVR2A or BMPR2 and activated SMAD2/3 through receptor complexes formed by ALK5 and ACVR2A, ACVR2B, or TGFBR2. Signaling through SMAD2/3 promoted the proliferation of germ cells, whereas that through SMAD1/5/8 directed the subsequent differentiation of spermatogonia. BMP8A promoted spermatogenesis in cultured mouse testis explants, and the resulting spermatids were functionally competent for fertilization. These results suggest that the dual role of BMP8A in promoting proliferation and differentiation of spermatogonia may be exploited clinically to treat male infertility.

Dopamine is a key catecholamine in the brain and the kidney, where it is involved in a number of physiological functions such as locomotion, cognition, emotion, endocrine regulation and renal function. As a membrane impermeant hormone and neurotransmitter, dopamine is thought to signal by binding and activating dopamine receptors, members of the G protein couple receptor (GPCR) family, only on the plasma membrane. Here, using novel nanobody-based biosensors, we demonstrate for the first time that the dopamine D1 receptor (D1DR), the primary mediator of dopaminergic signaling in the brain and kidney, not only functions on the plasma membrane but becomes activated at the Golgi apparatus in the presence of its ligand. We present evidence that activation of the Golgi pool of D1DR is dependent on Organic Cation Transporter 2 (OCT2), a dopamine transporter, providing an explanation for how the membrane impermeant dopamine accesses subcellular pools of D1DR. We further demonstrate that dopamine activates Golgi-D1DR in murine striatal medium spiny neurons (MSN) and this activity depends on OCT2 function. We also introduce a new approach to selectively interrogate compartmentalized D1DR signaling by inhibiting Gas coupling, using a nanobody-based chemical recruitment system. Using this strategy, we show that Golgi-localized D1DRs regulate cAMP production and mediate local protein kinase A activation. Together, our data suggest that spatially compartmentalized signaling hubs are previously unappreciated regulatory aspects of D1DR signaling. Our data provide further evidence for the role of transporters in regulating subcellular GPCR activity.

Lin TY, Wu FJ, Lee WY, Hsiao CL, Luo CW. Ovarian regulation of neuromedin U and its local actions in the ovary, mediated through neuromedin U receptor 2. Am J Physiol Endocrinol Metab 304: E800-E809, 2013. First published February 19, 2013 doi:10.1152/ajpendo.00548.2012.-Neuromedin U (NMU) was originally identified as an anorexigenic peptide that modulates appetite as well as energy homeostasis through the brain-gut axis. Although growing evidence has linked NMU activity with the development of female reproductive organs, no direct expression of and function for NMU in these organs has been pinpointed. Using a superovulated rat model, we found that NMU is directly expressed in the ovary, where its transcript level is tightly regulated by gonadotropins. Ovarian microdissection and immunohistochemical staining showed clearly that NMU is expressed mainly in theca/interstitial cells and to a moderate extent in granulosa cells. Primary cell studies together with reporter assays indicated the Nmu mRNA level in these cells is strongly induced via cAMP signaling, whereas this increase in expression can be reversed by the degradation message residing within its 3=-untranslated region, which recruits cis-acting mRNA degradation mechanisms, such as the gonadotropininduced zinc finger RNA-binding protein Zfp36l1. This study also demonstrated that NMUR2, but not NMUR1, is the dominant NMU receptor in the ovary, where its expression is restricted to theca/ interstitial cells. Treatment with NMU led to induction of the early response c-Fos gene, phosphorylation of extracellular signal-regulated kinase 1/2, and promotion of progesterone production in both developing and mature theca/interstitial cells. Taken as a whole, this study demonstrates that NMU and NMU receptor 2 compose a novel autocrine system in theca/interstitial cells in which the intensity of signaling is tightly controlled by gonadotropins. adenosine 3=,5=-cyclic monophosphate; theca/interstitial cells NEUROMEDIN U (NMU) is a neuropeptide first isolated from the porcine spinal cord and was named based on its strong ability to cause uterine muscle contraction (31). Following its initial isolation, NMU has been subsequently identified in rats (7, 30), frogs (9), chickens (33), humans (2), and other vertebrates (5) with a diverse length due to there being different locations for its endoproteolytic sites in each propeptide. Despite this, mature NMU peptides across species display a remarkable amino acid identity in their COOH-terminal pentapeptide (Phe-ArgPro-Arg-Asn-NH 2 ), suggesting that this region is important to receptor binding and biological activity (37).NMU has not been detected in circulating blood, and therefore it has been proposed to act more as a local regulator than as a circulating hormone (8). Distribution of NMU was later reported to be ubiquitous, with higher expression in the pituitary gland, gastrointestinal tract, thyroid gland, ovary, and spinal cord (8,11). In contrast to this wide distribution, the two NMU receptors, NMUR1 and NMUR2, show ...

No abstract