CILK1 (ciliogenesis associated kinase 1) is a serine/threonine protein kinase essential for primary cilium biogenesis and function 1. The kinase requires dual phosphorylation of its TDY motif for activation and phosphorylates multiple substrates including ERK1 to regulate ciliary length and intraflagellar transport (IFT) speed in a cAMP and mTORC1-dependent manner 2. CILK1's intrinsically disordered C-terminal region mediates interaction with the scaffold protein KATNIP, which potentiates CILK1 activation and enhances its control of primary cilia 3. Functionally, CILK1 regulates ciliary localization of Sonic Hedgehog pathway components and IFT machinery at ciliary tips, negatively controlling cilium length and ciliation rate 4. CLINICAL SIGNIFICANCE: Mutations in CILK1 cause multiple ciliopathies. Homozygous kinase-domain mutations cause lethal skeletal dysplasias and endocrine-cerebroosteodysplasia 5, while non-catalytic domain variants associate with cranioectodermal dysplasia featuring skeletal abnormalities, renal failure, and liver fibrosis 5. A point mutation (A615T) in the C-terminal region causes juvenile myoclonic epilepsy through impaired KATNIP-mediated regulation and defective Hedgehog signaling 6. Beyond ciliopathies, CILK1 overexpression promotes breast cancer proliferation and chemoresistance via ERK1 phosphorylation, suggesting therapeutic potential for CILK1 inhibitors 2.