CDKL5 targets containing the consensus motif (yellow), phosphorylation targets of CDKL5 without the consensus motif or phosphorylation site not specifically determined (red) and associated proteins (purple). (A) CEP131 is a key component of centriolar satellites that are critical to primary cilia function among a range of critical cell functions. (B) MAP1S and EB2 are known direct targets of CDKL5 involved in neuronal microtubule dynamics, which may, in turn, affect microtubule dynamic instability or microtubule trafficking of cargo in neurons. (C) ARHGEF2 and DLG5 are both direct CDKL5 targets. ARHGEF2 can bind to microtubules and is involved in maintaining processes critical to neurons including regulation of dendritic spine morphology and focal adhesions. DLG2 controls dendritic spine formation and synaptic transmission in cortical neurons by modulating the localization of N-cadherin (CDH2). Other proteins CDKL5 may interact with or potentially phosphorylate include SHTN1, CLIP170 and IQGAP1. (D) DNA damage induces CDKL5 re-localization to sites of double-stranded DNA breaks (DSB). Here CDKL5 phosphorylates the direct targets ELOA, TDN1 and EP400, leading to transcriptional silencing in the region of the DSB and subsequently affects transcriptional activity. (E) Other potential phosphorylation targets of CDKL5 not containing the consensus motif include the chromatin remodeling proteins MeCP2, DNMT1 and HDAC4, and transcription factor SOX9 and the signal transduction protein SMAD3, all may affect transcriptional control, regulate cell identity and determine cell fate. (F) AMPH1 is a direct CDKL5 phosphorylation target, and phosphorylation prevents the association with endophilin (ENDO) and dynamin (DNM1), inhibiting clathrin-mediated endocytosis. This is critical for synaptic vesicle recycling, spine formation and axonal growth. There is evidence CDKL5 may phosphorylate the cell adhesion molecule NGL1, which interacts with palmitoylated PSD95 and this provides a scaffold for receptors of glutamatergic synapses. Created with BioRender.com.