Identification Of The Interaction Between Rap1GAP And Glia Cell Line-derived Neurotrophic Factor Receptor Ret

Glia cell line-derived neurotrophic factor (GDNF) family contains four members: GDNF, NRTN (neurturin), ARTN (artemin), PSPN (persephin), which could not only support the survival and development of mesencephalic dopaminergic neuron and motoneuron in the central nervous system, but also enhance the survival and differentiation of sympathetic and parasympathetic neuron, sensory neuron and enteric neuron in the peripheral nervous system. GDNF is also an important morphologic factor involved in the development of the kidney and plays a key role in the differentiation of spermatogonial cells. GDNF family ligands mediate signaling pathway through their coreceptors GFRal-4 and Ret, belonging to the receptor kinase family. After binding with their ligands, GFRal-4 would trigger the autophosphorylation of Ret and then activate the downstream signaling pathway such as Ras/MAPK, PI3-K and PLCγ etc. The intracellular domain of Ret, with the tyrosine kinase activity, provides the docking sites for many adaptor proteins. For example, the pY1062 in Ret could at least bind to five docking proteins, such as She, FRS2, DOK4/5, IRS1/2 and enigma, to induce different downstream signaling pathway either leading to neuronal growth or branching.Rap1GAP, a molecular weight-89kDa protein which identified in 1991, was the first protein for which a specific GAP activity towards Rap1. Rap1 belongs to the Ras subfamily of small GTPases and with 53% amino-acid identity to Ras. Like other small GTPases members, rapl is in activated state when bound GTP, and in inactivated state when bound GDP. The nucleotide-loading state is tightly regulated by guanine nucleotide exchange factors (GEFs) that catalyse the dissociation of bound nucleotide, and GTPase activating proteins (GAPs) which accelerate the hydrolysis of bound GTP. A core domain comprising 340 amino acids (75-415) was shown to be necessary and sufficient for this GAP activity. Rap1GAP has been recently reported to be involved in the enlargement of dendrite spine head through inhibiting Rapl...