Fig. 2.

The Reelin-Disabled 1 signaling pathway. Binding of Reelin to its receptors, VLDLR and ApoER2, induces SFK activation and Dab1 tyrosine phosphorylation. Phosphorylated Dab1 acts as a hub to recruit different downstream SH2 domain-containing proteins including Crk, Nckβ, p85 (PI3K) and SOCS. Dab1–Crk interaction activates the downstream C3G-Rap1 pathway. Activated Rap1 then regulates the membrane distribution of N-cadherin. Recruitment of Nckβ to Dab1 is likely involved in actin remodeling through p130Cas. The association of PI3K p85 subunit with Dab1 activates the PI3K-Akt pathway, which in turn modulates the phosphorylation of microtubule binding proteins, tau and MAP1B, leading to microtubule remodeling. Activation of PI3K-Akt may engage LIMK1 and n-cofilin, resulting in stabilization of actin polymerization. In contrast, Dab1–SOCS association down-regulates Reelin signaling by degrading phosphorylated Dab1 through the ubiquitin proteasome system, resulting in termination of Reelin signaling. The interaction between tyrosine-phosphorylated Dab1 and Lis1 also causes microtubule remodeling. Reelin-Dab1 signaling and LKB-STRAD-Stk25 play opposing roles in regulating the rearrangement of the Golgi apparatus and neuronal polarity