Fig. 1. GDNF-family ligand interaction with their receptors. (A) A dimer of GDNF brings together two molecules of GFR1. This complex dimerizes two molecules of Ret leading to transphophorylation of their tyrosine kinase domains. (B) All GFLs activate RET tyrosine kinase via different GFR receptors. Solid arrows indicate the preferred functional ligand-receptor interactions, whereas dotted arrows indicate putative crosstalk. GFR proteins are attached to the plasma membrane through a GPI-anchor and consist of three (GFR4 has only two) globular cysteine-rich domains joined together by adapter sequences. Ca²⁺ ions bound to one of the four extracellular cadherin-like domains of RET are needed for its activation by GFLs.