The roles of Midkine/Alk signaling in sympathetic neurons physiologically and pathologically

     Neuroblastoma(NB) is the most common extracranial solid cancer that arises in immature nerve cells, and thus often occurs in childhood and infancy, with an incidence of about 650 new cases per year in US. Some evidences suggested that disposition and process of NB may be associated to proliferation of immature sympathetic neurons regulated by some transcription factors.
      Recently, in some familial cases of NB, predisposing ALK mutations were observed, and constitutively activation of mutant ALK induced cell proliferation independent of ligand binding[1]. Moreover, in NB cells that express mutated ALK, downregulation of ALK expression caused by shRNA-mediatedand and pharmacological kinase inhibition both lead to strongly reduction of cell proliferation and promotion of cell death. Accordingly, investigators begin to focus on the role and mechanism of ALK signaling in the sympathetic neuron lineage and the developing nervous system.
     In the experiment by Reiff et al., results show that expression of constitutively active ALK mutations and ALKwt overexpression both lead to increased proliferation of sympathetic neurons. When treated with pharmacological Alk kinase inhibitor NVP-TAE684 and Alk siRNA, the sympathetic neuron cells show the reduced proliferation. It is reported previously, Midkine and Ptn as Alk ligands show the ability to result in phosphorylation of Alk and the downstream kinase PI3K. Knockdown of Midkine mRNA levels by siRNA strongly decreases the proliferation of immature neurons, and the effect is rescued by overexpression of mutated ALK, suggesting that midkine dependent Alk signaling controls proliferation of sympathetic neurons. Further study on mechanism is carried out. The results indicate that regulation of Alk expression in sympathetic neurons is mediated by Hand2 and Alk signaling increases the expression of two additional proliferation regulators, NMyc and trkB[2].
     In summary, Mk/Alk signaling is involved in the regulation of sympathetic neurogenesis, and ALK mutations can damage the normal neurogenesis and thus lead to predisposition for NB. The ALK signaling may be potential target against neuroblastoma.

[1]. Nature 2008; 455, 930-935.
[2]. Development 2011; 138, 4699-4708. 

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S1108 TAE684 (NVP-TAE684) TAE684 (NVP-TAE684) is a potent and selective ALK inhibitor with IC50 of 3 nM in a cell-free assay, 100-fold more sensitive for ALK than InsR. (39) (4)

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