Figure 3.

Involvement of the PAK1 pathway in developmental phenotypes. RAC1 and CDC42 are direct activators, TRIO and HACE1 are indirect (via RAC1) regulators of PAK1. ARHGEF6 binds PAK1 for regulation of neurite outgrowth. PAK1 activates LIMK1, the regulator of PAK1 downstream effectors cofilin (CFL2) and tubulin cofactor B. Disorders associated with deactivating and/or activating variants for each gene are indicated in grey with the respective mode of inheritance given (see Supplementary Table 2 for details and phenotypic overlap). Green shaded box indicates activation of RAC1-PAK1-LIMK1 pathway in FXS, where macrocephaly also occurs. Currently available inhibitors of PAK1 are indicated.