Cyclic AMP (cAMP) is an important intracellular signalling mediator. It is generated in mammals by nine membrane-bound and one soluble adenylyl cyclases (ACs), each with distinct regulation and expression patterns. Although many drugs inhibit or stimulate AC activity through the respective upstream G-protein coupled receptors (for example, opioid or beta-adrenergic receptors), ACs themselves have not been major drug targets. Over the past decade studies on the physiological functions of the different mammalian AC isoforms as well as advances in the development of isoform-selective AC inhibitors and activators suggest that ACs could be useful drug targets. Here we discuss the therapeutic potential of isoform-selective compounds in various clinical settings, including neuropathic pain, neurodegenerative disorders, congestive heart failure, asthma and male contraception.

Metastasis is the primary cause of cancer death. Weichand et al. describe a new mechanism explaining how tumor-associated macrophages contribute to metastatic spread, which involves promoting tumor lymphangiogenesis via S1P receptor 1 and the NLRP3 inflammasome.

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Plant defense against pests and pathogens is known to be conferred by either salicylic acid (SA) or jasmonic acid (JA)/ethylene (ET) pathways, depending on infection or herbivore-grazing strategy. It is well attested that SA and JA/ET pathways are mutually antagonistic allowing defense responses to be tailored to particular biotic stresses. Nitric oxide (NO) has emerged as a major signal influencing resistance mediated by both signaling pathways but no attempt has been made to integrate NO into established SA/JA/ET interactions. NO has been shown to act as an inducer or suppressor of signaling along each pathway. NO will initiate SA biosynthesis and nitrosylate key cysteines on TGA-class transcription factors to aid in the initiation of SA-dependent gene expression. Against this, S-nitrosylation of NONEXPRESSOR OF PATHOGENESIS-RELATED PROTEINS1 (NPR1) will promote the NPR1 oligomerization within the cytoplasm to reduce TGA activation. In JA biosynthesis, NO will initiate the expression of JA biosynthetic enzymes, presumably to over-come any antagonistic effects of SA on JA-mediated transcription. NO will also initiate the expression of ET biosynthetic genes but a suppressive role is also observed in the S-nitrosylation and inhibition of S-adenosylmethionine transferases which provides methyl groups for ET production. Based on these data a model for NO action is proposed but we have also highlighted the need to understand when and how inductive and suppressive steps are used.

The Drosophila Sprouty (SPRY) protein has been shown to inhibit the actions of epidermal growth factor and fibroblast growth factor. However, the role of mammalian SPRY proteins has not been clearly elucidated. We postulated that human Sprouty2 (hSPRY2) is an inhibitor of cellular migration and proliferation. Indeed, using stably transfected HeLa cells, which expressed hemagglutinin (HA)-tagged hSPRY2 or hSPRY2 tagged at the C terminus with red fluorescent protein, we demonstrated that hSPRY2 inhibits the migration of cells in response to serum, epidermal growth factor, fibroblast growth factor, and platelet-derived growth factor. Additionally, hSPRY2 also inhibited the growth of HeLa cells in response to serum. Previously, two C-terminal domains on hSPRY2, which are necessary for its colocalization with microtubules (residues 123-177) or translocation to membrane ruffles (residues 178 -194), have been identified (Lim, J., Wong, E. S., Ong, S. H., Yusoff, P., Low, B. C., and Guy, G. R. (2000) J. Biol. Chem. 275, 32837-32845). Therefore, using TAT-tagged hSPRY2 and its mutants, we determined the role of these two Cterminal domains in the inhibition of cell migration and proliferation. Our data show that the deletion of either of these two regions in hSPRY2 abrogates its ability to modulate cell migration in response to different growth factors and proliferation in response to serum. Therefore, we conclude that hSPRY2 inhibits the actions of a number of growth factors, and its C terminus, which is homologous among various SPRY isoforms, is important in mediating its biological activity.In Drosophila, Sprouty has been demonstrated to be important in regulating fibroblast growth factor (FGF) 1 and epidermal growth factor (EGF)-mediated cellular actions. Thus, in Drosophila Sprouty mutants, the fibroblast growth factor pathway is overactive, and excessive branching is seen in Drosophila airways (1). Kramer et al. (2) have shown antagonistic actions of Sprouty on both the FGF and EGF signaling pathways in Drosophila, where loss of Sprouty results in supernumerary neurons and glia. In addition, overexpression of Sprouty in wing veins and ovarian follicle cells, tissues where EGF signaling is required for proper patterning, results in phenotypes that resemble the loss-of-function phenotypes of EGF receptors (3, 4). Sprouty has also been shown to interfere with chick embryo development. Hence, infection of the prospective wing territory with a retrovirus containing the Sprouty gene inhibits proper limb growth and formation in the embryonic chick (5). Taken together, these results suggest that Sprouty acts as an antagonist of both FGF and EGF receptor signaling pathways.To date, four isoforms of mammalian Sprouty protein have been described (SPRY1-SPRY4) (1, 4-6). Among these, only partial clones of SPRY1 and SPRY3 are available. The mouse as well as human SPRY2 (hSPRY2) and mouse SPRY4 have been cloned (4, 6, 7), and both these proteins share considerable sequence homology in the C terminus. However, their N termini are...