NRTN, PAK1, JNK(MAPK8-10), NF-kB, MKK7 (MAP2K7), c-Raf-1, DAG, AKT(PKB), IKK (cat), PSPN, IKK-alpha, IP3, 220.127.116.11, GAB2, GFRalpha1, Erk (MAPK1/3), PI3K cat class IA, PtdIns(3,4,5)P3, c-Jun, GFRalpha2, GDNF, IRS-1, c-Src, 18.104.22.168, p120GAP, Shc, H-Ras, ARTN, SOS, GFRalpha3, ENIGMA, I-kB, FRS2, GFRalpha4, MEKK1(MAP3K1), p90Rsk, PLC-gamma, PI3K reg class IA (p85), DOK1, GRB2, NCK1, PtdIns(4,5)P2, CREB1, MEK1(MAP2K1), MEK2(MAP2K2), RET
GDNF family signaling
Glial cell line-derived neurotrophic factors (GDNF family), a group of structurally and functionally related polypeptides are involved in the control of neuron survival and differentiation, kidney morphogenesis, and spermatogonial cell fate .
GDNF family ligands include GDNF, Neurturin ( NRTN ), Artemin ( ARTN ) and Persephin ( PSPN ). They signal through GDNF family receptor alpha ( GFRalpha ), and Ret proto-oncogene ( RET ) with tyrosine kinase activity. Four different GFRalpha receptors have been characterized ( GFRalpha1, GFRalpha2, GFRalpha3, GFRalpha4 ), which determine the ligand specificity of the GFRalpha/ RET complex. GDNF binds to GFRalpha1, then forms a complex with RET. NRTN binds to GFRalpha2, ARTN to GFRalpha3, and PSPN activates RET by binding to GFRalpha4. NRTN and ARTN can crosstalk weakly with GFRalpha1, and GDNF with GFRalpha2. GDNF s bind to lipid-anchored GFRalpha and induce RET homodimerization and tyrosine autophosphorylation. Once phosphorylated, tyrosine residues in the intracellular domain of activated RET serve as high affinity binding sites for various intracellular signaling proteins in the target cells, such as adaptor proteins SHC transforming protein ( Shc ), Fibroblast growth factor receptor substrate 2 ( FRS2 ), Downstream of tyrosine kinase 1 ( DOK1 ), Downstream of tyrosine kinase 4 and 5 (IRS5(DOK4) and IRS6(DOK5)), Insulin receptor substrate 1 and 2 ( IRS-1 and IRS-2) and PDZ and LIM domain 7 (ENIGMA). RET can also recruit Phospholipase C gamma ( PLC-gamma ) and V-src sarcoma viral oncogene homolog ( c-Src ) .
RET activates several intracellular signaling cascades, which regulate cell survival, 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 (with presumable molecular signal participants v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( 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 ) by Growth factor receptor-bound protein 2 ( GRB2 )/ SHC transforming protein ( Shc ) adaptor proteins. Interaction of Shc with Gab2 and with regulatory 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 .
Activation of the PI3K/AKT and Ras/ERK pathways results in the activation of two transcription factors, Nuclear factor kappaB ( NF-kB ) and cAMP responsive element binding protein 1 ( CREB1 ), respectively .
DOK1 is a docking protein for the RET tyrosine kinase. DOK1 recruits GTPase activating protein RAS p21 protein activator 1 ( p120GAP ), which increase hydrolysis and inactivates H-Ras. Hereby DOK1 participates in attenuation of ERK activation. On the other hand DOK1 bounds to the NCK adaptor protein 1 ( NCK1 ) adaptor protein leads to Mitogen-activated protein kinase 8, 9 and 10 ( JNK(MAPK8-10) ) and Jun oncogene ( c-Jun ) activation .