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Paige Taylor, S.,Kunova Bosakova, Michaela,Varecha, Miroslav,Balek, Lukas,Barta, Tomas,Trantirek, Lukas,Jelinkova, Iva,Duran, Ivan,Vesela, Iva,Forlenza, Kimberly N.,Martin, Jorge H.,Hampl, Ales,Bamsha IRL Press 2016 Human molecular genetics Vol.25 No.18
<P>Mutations in several genes affecting cilia function cause SRPS, revealing a role for cilia function in skeletal development. To identify additional SRPS genes and discover novel ciliary molecules required for normal skeletogenesis, we performed exome sequencing in a cohort of patients and identified homozygosity for a missense mutation, p. E80K, in Intestinal Cell Kinase, ICK, in one SRPS family. The p. E80K mutation abolished serine/threonine kinase activity, resulting in altered ICK subcellular and ciliary localization, increased cilia length, aberrant cartilage growth plate structure, defective Hedgehog and altered ERK signalling. These data identify ICK as an SRPS-associated gene and reveal that abnormalities in signalling pathways contribute to defective skeletogenesis.</P>
Kunova Bosakova, Michaela,Nita, Alexandru,Gregor, Tomas,Varecha, Miroslav,Gudernova, Iva,Fafilek, Bohumil,Barta, Tomas,Basheer, Neha,Abraham, Sara P.,Balek, Lukas,Tomanova, Marketa,Fialova Kucerova, J National Academy of Sciences 2019 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.116 No.10
<▼1><P><B>Significance</B></P><P>A properly functioning primary cilium is prerequisite for both normal development and aging of all ciliated organisms, including humans. In vertebrates, the signaling of Hedgehog family morphogens depends entirely on primary cilium. Recently, we reported that fibroblast growth factors (FGF) signaling interacts with that of Hedgehog, and that this is a consequence of FGF regulating length of the cilium and speed of processes that happen therein. In this report, we provide a molecular mechanism of such interaction, identifying intestinal cell kinase as a mediator of the FGF-induced changes in the ciliary morphology and function. This expands our understanding how FGF signaling regulates intracellular processes, and how aberrant FGF signaling contributes to diseases, such as achondroplasia and cancer.</P></▼1><▼2><P>Vertebrate primary cilium is a Hedgehog signaling center but the extent of its involvement in other signaling systems is less well understood. This report delineates a mechanism by which fibroblast growth factor (FGF) controls primary cilia. Employing proteomic approaches to characterize proteins associated with the FGF-receptor, FGFR3, we identified the serine/threonine kinase intestinal cell kinase (ICK) as an FGFR interactor. ICK is involved in ciliogenesis and participates in control of ciliary length. FGF signaling partially abolished ICK’s kinase activity, through FGFR-mediated ICK phosphorylation at conserved residue Tyr15, which interfered with optimal ATP binding. Activation of the FGF signaling pathway affected both primary cilia length and function in a manner consistent with cilia effects caused by inhibition of ICK activity. Moreover, knockdown and knockout of ICK rescued the FGF-mediated effect on cilia. We provide conclusive evidence that FGF signaling controls cilia via interaction with ICK.</P></▼2>