Figure 3. Cis versus trans signaling of RET activation.

(a) In the cis model of RET activation. GPI-anchored GFRa dinrers. located into lipid rafts, first bind a GDNF dinrer with high affinity. RET is then recruited to the GDNF-GFRa complex within the raft compartment. (b) GDNF binds to soluble GFRa in the trans model of RET activation. The GDNF-GFRa complex is then presented to RET, triggering RET activation. Activated RET preferentially associates with SHC outside the rafts, and predominantly associates with FRS2 within the rafts. Unphosphorylated (Y) and phosphorylated (Y*) tyrosine residues are indicated.

in a strictly regulated manner. GPI-linked GFRa proteins cluster into lipid rafts and recruit RET to lipid rafts after GDNF stimulation (Figure 3a). This recruitment of RET to rafts (through cis signaling) is independent on RET kinase activity. An alternative model for RET activation has been suggested by Paratcha and coworkers (Paratcha, G. et al., 2001; Manie, S. et al., 2001) (Figure 3b). Previously, soluble forms of GFRa were shown to be able to bind GDNF family ligands and to activate RET in trans (Jing, S. et al., 1996; Treanor, J. J. et al., 1996). A biologically active, soluble form of has been detected in the conditioned medium of neuronal and glial cell cultures (Worley, D. S. et al., 2000; Paratcha, G. et al., 2001). In the alternative pathway for RET activation, GDNF binds to soluble GFRa. The GDNF-GFRa complex is then presented to RET, triggering RET activation (through trans signaling). Transactivated RET is located initially outside the raft compartment and subsequently recruited to the lipid compartment through a process requiring the catalytic activity of the receptor. Of note, this differential compartmentalization of activated RET can trigger different signaling pathways. Raft-located RET preferentially associates with the adaptor FRS2 leading to sustained ERK activation, whereas RET located outside the rafts associates with SHC and leads to transient activation of ERK and activation of PI3K/AKT pathway (Paratcha, G. et al., 2001).

The intracellular domain of RET contains 14 tyrosine residues in the long and 12 in the short isoform, the latter lacking two tyrosine residues in the C-terminus. Interactions of RET with a number of downstream targets have been identified (Figure 4).

Phosphorylated tyrosine residues Tyr905, Tyr1015 and Tyr1096, the latter long isoform-specific, have been identified as docking sites for the adaptor proteins GRB7/GRB10, Phospholipase-Cy and GRB2, respectively (Pandey, A. et al., 1995; Pandey, A. et al., 1996; Borrello, M. G. et al., 1996; Alberti, L. et al., 1998). Tyr1062 is a multidocking site interacting with a number of transduction molecules: SHC, FRS2, IRS 1/2, DOK proteins, ENIGMA and PKCa (Durick, K. et al., 1996; Arighi, E. et al., 1997; Lorenzo, M. J. et al., 1997; Kurokawa, K. et al., 2001; Melillo, R. M. et al., 2001; Hennige, A. M. et al., 2000; Grimm, J. et al., 2001; Andreozzi, F. et al., 2003). The binding of SHC, FRS2, IRS1/2 and DOK to Tyr1062 is dependent on phos-phorylation of this residue and is mediated by PTB or SH2 phosphotyrosine binding rh f Y-1015

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