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Development GDNF family signaling


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Development GDNF family signaling

GDNF family signaling

Glial cell line-derived neurotrophic factors (GDNF family), a group of structurallyand functionally related polypeptides are involved in the control of neuron survival anddifferentiation, kidney morphogenesis, and spermatogonial cell fate [1].

GDNF family ligands include GDNF, Neurturin ( NRTN ), Artemin (ARTN ) and Persephin ( PSPN ). They signal through GDNF family receptoralpha ( GFRalpha ), and Ret proto-oncogene ( RET ) with tyrosine kinaseactivity. Four different GFRalpha receptors have been characterized (GFRalpha1, GFRalpha2, GFRalpha3, GFRalpha4 ), whichdetermine the ligand specificity of the GFRalpha/ RET complex. GDNFbinds to GFRalpha1, then forms a complex with RET. NRTN binds toGFRalpha2, ARTN to GFRalpha3, and PSPN activates RETby binding to GFRalpha4. NRTN and ARTN can crosstalk weakly withGFRalpha1, and GDNF with GFRalpha2. GDNF s bind tolipid-anchored GFRalpha and induce RET homodimerization and tyrosineautophosphorylation. Once phosphorylated, tyrosine residues in the intracellular domainof activated RET serve as high affinity binding sites for various intracellularsignaling proteins in the target cells, such as adaptor proteins SHC transforming protein( Shc ), F ibroblast growth factor receptor substrate 2 ( FRS2 ),Downstream of tyrosine kinase 1 ( DOK1 ), Downstream of tyrosine kinase 4 and 5(IRS5(DOK4) and IRS6(DOK5)), I nsulin receptor substrate 1 and 2 ( IRS-1 andIRS-2) and PDZ and LIM domain 7 (ENIGMA ). RET can also recruit Phospholipase Cgamma ( PLC-gamma ) and V-src sarcoma viral oncogene homolog ( c-Src )[1].

RET activates several intracellular signaling cascades, which regulate cellsurvival, differentiation, proliferation, migration, chemotaxis, branching morphogenesis,neurite outgrowth, and synaptic plasticity.

Activation of RET initiates signal transduction pathways via adaptor protein.Activation of Extracellular signal-regulated kinases ( ERK ) pathway (withpresumable molecular signal participants v-Ha-ras Harvey rat sarcoma viral oncogenehomolog ( H-RAS )/V-raf-1 murine leukemia viral oncogene homolog ( c-Raf )/Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 and MEK2 )/ERK ) occurs through recruitment of Son of sevenless homolog ( SOS ) byGrowth factor receptor-bound protein 2 ( GRB2 )/ SHC transforming protein (Shc ) adaptor proteins. Interaction of Shc with Gab2 and withregulatory subunits of Phosphoinositide-3-kinase ( PI3K reg class IA (p85) )results in activation of PI3K/V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB) ) pathway leading to cell survival [2].

Activation of the PI3K/AKT and Ras/ERK pathways results in the activation of twotranscription factors, Nuclear factor kappaB ( NF-kB ) and cAMP responsive elementbinding protein 1 ( CREB1 ), respectively [3].

DOK1 is a docking protein for the RET tyrosine kinase. DOK1recruits GTPase activating protein RAS p21 protein activator 1 ( p120GAP ), whichincrease hydrolysis and inactivates H-Ras. Hereby DOK1 participates inattenuation of ERK activation. On the other hand DOK1 bounds to the NCKadaptor protein 1 ( NCK1 ) adaptor protein leads to Mitogen-activated proteinkinase 8, 9 and 10 ( JNK(MAPK8-10) ) and Jun oncogene ( c-Jun ) activation[4].