Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Netrin-1 is known to function as a chemoattractant for several classes of developing axons and as a chemorepellent for other classes of axons, apparently dependent on the receptor type expressed by responsive cells. In culture, growth cones of embryonic Xenopus spinal neurons exhibited chemoattractive turning toward the source of netrin-1 but showed chemorepulsive responses in the presence of a competitive analog of cAMP or an inhibitor of protein kinase A. Both attractive and repulsive responses were abolished by depleting extracellular calcium and by adding a blocking antibody against the netrin-1 receptor Deleted in Colorectal Cancer. Thus, nerve growth cones may respond to the same guidance cue with opposite turning behavior, dependent on other coincident signals that set the level of cytosolic cAMP.
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PMID:cAMP-dependent growth cone guidance by netrin-1. 942 46

Edotecarin (PHA-782615; formerly J-107088) is a derivative of NB-506, an indolocarbazole antitumor agent. It is a novel inhibitor of topoisomerase I that induces single-strand DNA cleavage more effectively than NB-506 or camptothecin (CPT) and at different DNA sequences. The DNA-topoisomerase I complexes induced by edotecarin are more stable than those occurring after exposure to CPT or NB-506. The antitumor activity of edotecarin is less cell cycle dependent than other topoisomerase I inhibitors. Being an indolocarbazole, it is structurally related to staurosporine but does not possess protein kinase inhibitory properties. In addition, edotecarin does not form active metabolites and is not a substrate for in vitro P450-mediated metabolism. The antitumor activity of edotecarin has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in breast, cervix, pharynx, lung, prostate, colon, gastric, and hepatic cancer models. Edotecarin is effective on cells that have acquired resistance related to P-glycoprotein. In vitro synergy has been demonstrated when edotecarin was tested in combination with cisplatin, 5-fluorouracil, etoposide, paclitaxel, doxorubicin, vincristine, CPT, and gemcitabine. Three phase I and 5 phase II studies have been carried out to date. Combination studies of edotecarin with other chemotherapeutic agents are in current clinical trials. The primary dose-limiting toxicities were grade 3/4 neutropenia and febrile neutropenia. Dose-limiting diarrhea was observed only with a twice-weekly administration schedule. Recent progress in preclinical and clinical studies of edotecarin is reviewed.
Clin Colorectal Cancer 2005 May
PMID:Edotecarin: a novel topoisomerase I inhibitor. 1592 4

The netrin-1 receptor Deleted in Colorectal Cancer (DCC) is required for the formation of major axonal projections by embryonic cortical neurons, including the corpus callosum, hippocampal commissure, and cortico-thalamic tracts. The presentation of DCC by axonal growth cones is tightly regulated, but the mechanisms regulating DCC trafficking within neurons are not well understood. Here, we investigated the mechanisms regulating DCC recruitment to the plasma membrane of embryonic cortical neurons. In embryonic spinal commissural neurons, protein kinase A (PKA) activation recruits DCC to the plasma membrane and enhances axon chemoattraction to netrin-1. We demonstrate that PKA activation similarly recruits DCC and increases embryonic cortical neuron axon extension, which, like spinal commissural neurons, respond to netrin-1 as a chemoattractant. We then determined if depolarization might recruit DCC to the plasma membrane. Neither netrin-1 induced axon extension, nor levels of plasma membrane DCC, were altered by depolarizing embryonic spinal commissural neurons with elevated levels of KCl. In contrast, depolarizing embryonic cortical neurons increased the amount of plasma membrane DCC, including at the growth cone, and increased axon outgrowth evoked by netrin-1. Inhibition of PKA, phosphatidylinositol-3-kinase, protein kinase C, or exocytosis blocked the depolarization-induced recruitment of DCC and suppressed axon outgrowth. Inhibiting protein synthesis did not affect DCC recruitment, nor were the distributions of trkB or neural cell adhesion molecule (NCAM) influenced by depolarization, consistent with selective mobilization of DCC. These findings identify a role for membrane depolarization modulating the response of axons to netrin-1 by regulating DCC recruitment to the plasma membrane.
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PMID:Depolarization recruits DCC to the plasma membrane of embryonic cortical neurons and enhances axon extension in response to netrin-1. 1869 85

Navigation of retinal projections towards their targets is regulated by guidance molecules and growth cone transduction mechanisms. Here, we present in vitro and in vivo evidences that the cannabinoid receptor 2 (CB2R) is expressed along the retino-thalamic pathway and exerts a modulatory action on axon guidance. These effects are specific to CB2R since no changes were observed in mice where the gene coding for this receptor was altered (cnr2 (-/-)). The CB2R induced morphological changes observed at the growth cone are PKA dependent and require the presence of the netrin-1 receptor, Deleted in Colorectal Cancer. Interfering with endogenous CB2R signalling using pharmacological agents increased retinal axon length and induced aberrant projections. Additionally, cnr2 (-/-) mice showed abnormal eye-specific segregation of retinal projections in the dorsal lateral geniculate nucleus (dLGN) indicating CB2R's implication in retinothalamic development. Overall, this study demonstrates that the contribution of endocannabinoids to brain development is not solely mediated by CB1R, but also involves CB2R.
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PMID:Cannabinoid receptor CB2 modulates axon guidance. 2395 Oct 24