Dual-specificity phosphatases (DUSPs) are essential regulators of neuronal cell growth and differentiation by targeting proteins essential to neuronal survival in signaling pathways, among which the MAP kinases (MAPKs) stand out

Dual-specificity phosphatases (DUSPs) are essential regulators of neuronal cell growth and differentiation by targeting proteins essential to neuronal survival in signaling pathways, among which the MAP kinases (MAPKs) stand out. considered to be part of the high-risk NB group (about 40% of cases). Very low-, low-, and intermediate-risk NB patients show a 5-year survival of 90C95%, whereas high-risk NB patients show a 5-year survival of 40C50% [7,8,9]. The risk group determines the therapeutic treatment of NB patients, from observation or surgery alone for low-risk patients to multimodal therapy for high-risk patients. Multimodal therapy includes surgery, chemotherapy and radiotherapy, myeloablative therapy followed by bone marrow autologous transplantation, and immunotherapy and retinoic acid (RA)-based maintenance therapies. Current high-risk NB clinical trials are testing the efficacy of drugs targeting specific drivers of NB or major pro-oncogenic proteins. Included in these Mcl1-IN-2 are, amongst others, ALK and additional RTKs, the different parts of MYCN downstream pathways such as for example ornithine decarboxylase (ODC1), and the different parts of the PI3K/AKT/mTOR and RAS-ERK1/2 MAPK signaling pathways [10,11,12,13,14]. Familial NB makes up about 1C2% of NB instances, with two main genes displaying germline mutations in colaboration with the condition: the RTK gene, which can be indicated in the developing anxious program [15 primarily,16]; as well as the gene, which encodes a large-size atypical DUSP suggested to focus on MAPKs, were connected with low-risk NB [25,26]. With this review, we summarize the existing knowledge for the part of MAPK phosphatases (MKPs) and related small-size atypical DUSPS in NB, and their potential as NB drug and biomarker focuses on. 2. Neuroblastoma Cell Development and Differentiation NB can be viewed as a neural crest-related developmental cells disease where modifications in neuronal differentiation, powered from the unbalanced actions of pro-proliferative and pro-differentiation elements for the maturation and migration of neural crest cells and neuroblasts, play a simple etiologic part. Highly differentiated NB Mcl1-IN-2 tumors possess a favorable medical outcome, and spontaneous regression linked to neuroblast apoptosis is frequent even in metastatic cases [5,27,28,29]. amplification, the major hallmark of high-risk NB, associates with poorly differentiated NB tumors [30,31,32], and signaling through ALK favors proliferation and/or survival depending on the maturity of the neural cells [33,34]. In addition, activation of Mcl1-IN-2 the tyrosine kinase neurotrophin receptors TrkA and TrkB leads to apoptotic/differentiation neuroblast responses or to survival/proliferative effects, respectively [35,36,37]. Several animal models suitable to the FUT4 study of NB differentiation and transformation have been generated, mainly centered in amplification and ALK hyperactivation [38,39]. NB cell differentiation can also be triggered in vitro by culturing NB cells in the presence of differentiation factors, such as retinoids (retinoic acid, RA), phorbol esters (phorbol 12-myristate 13-acetate, PMA), and neurotrophins (nerve growth factor, NGF; brain-derived neurotrophic factor, BDNF) [40,41]. Human and rodent cell lines commonly used to study NB cell differentiation include SH-SY5Y and other derivatives from the SK-N-SH cell line, IMR-32, SMS-KCNR (all NB; human), Neuro2A (NB; mouse), PC12 (pheochromocytoma; rat), and P19 (embryonic teratocarcinoma; mouse) cell lines, among others. Extensive experimental work using these model systems has provided a picture in which the major signaling pathways involved in the molecular effects of MYCN and ALK in NB are the RAS/MAPK, PI3K/AKT, and JAK/STAT pathways [41,42,43,44] (Figure 1). Open in a separate window Figure 1 Schematic depiction of the major pathways involved in signaling through the ALK-MYCN axis in neuroblastoma (NB). ALK signals downstream mainly through the RAS-ERK1/2 MAP kinase (MAPK) pathway, as well as through the PI3K/AKT and JAK/STAT pathways, resulting in increased transcription and cell growth (straight dashed lines). Signaling through Trk neurotrophin receptors can be demonstrated also. MYCN transcriptional activity favorably feeds the pathway by advertising transcription (curved blue dotted lines), whereas transcriptional activity mediated from the MAPK nuclear effectors adversely feed-back the MAPK pathways by advertising the transcription of MAPK phosphatases (MKP) genes (curved reddish colored dotted range). Right solid lines indicate immediate dephosphorylation of proteins substrates by MKPs or by additional dual-specificity phosphatases (DUSPs). Dephosphorylation of MAPKs by MKPs can be well documented, whereas evidence for the dephosphorylation of Trks or STATs by additional DUSPs is bound. See text message for additional information. Genes linked to the RAS-ERK1/2 MAPK pathway screen somatic modifications in about 5% of sporadic major NB tumors, having a higher percentage of modifications (specifically in and genes) in relapsed NB examples acquired after chemotherapy [45,46,47]. This makes the RAS-ERK1/2 axis a potential reactive pathway for restorative treatment in NB. RAF-MEK1/2 or MEK1/2 pharmacological inhibitors shown great inhibitory development and success results, and.