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      Primary Cilium-Dependent Signaling Mechanisms

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          Abstract

          Primary cilia are hair-like organelles and play crucial roles in vertebrate development, organogenesis, health, and many genetic disorders. A primary cilium is a mechano-sensory organelle that responds to mechanical stimuli in the micro-environment. A cilium is also a chemosensor that senses chemical signals surrounding a cell. The overall function of a cilium is therefore to act as a communication hub to transfer extracellular signals into intracellular responses. Although intracellular calcium has been one of the most studied signaling messengers that transmit extracellular signals into the cells, calcium signaling by various ion channels remains a topic of interest in the field. This may be due to a broad spectrum of cilia functions that are dependent on or independent of utilizing calcium as a second messenger. We therefore revisit and discuss the calcium-dependent and calcium-independent ciliary signaling pathways of Hedgehog, Wnt, PDGFR, Notch, TGF-β, mTOR, OFD1 autophagy, and other GPCR-associated signaling. All of these signaling pathways play crucial roles in various cellular processes, such as in organ and embryonic development, cardiac functioning, planar cell polarity, transactivation, differentiation, the cell cycle, apoptosis, tissue homeostasis, and the immune response.

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          Most cited references95

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          Patched1 regulates hedgehog signaling at the primary cilium.

          Primary cilia are essential for transduction of the Hedgehog (Hh) signal in mammals. We investigated the role of primary cilia in regulation of Patched1 (Ptc1), the receptor for Sonic Hedgehog (Shh). Ptc1 localized to cilia and inhibited Smoothened (Smo) by preventing its accumulation within cilia. When Shh bound to Ptc1, Ptc1 left the cilia, leading to accumulation of Smo and activation of signaling. Thus, primary cilia sense Shh and transduce signals that play critical roles in development, carcinogenesis, and stem cell function.
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            The vertebrate primary cilium in development, homeostasis, and disease.

            Cilia are complex structures that have garnered interest because of their roles in vertebrate development and their involvement in human genetic disorders. In contrast to multicellular invertebrates in which cilia are restricted to specific cell types, these organelles are found almost ubiquitously in vertebrate cells, where they serve a diverse set of signaling functions. Here, we highlight properties of vertebrate cilia, with particular emphasis on their relationship with other subcellular structures, and explore the physiological consequences of ciliary dysfunction.
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              The Notch signalling system: recent insights into the complexity of a conserved pathway.

              Notch signalling links the fate of one cell to that of an immediate neighbour and consequently controls differentiation, proliferation and apoptotic events in multiple metazoan tissues. Perturbations in this pathway activity have been linked to several human genetic disorders and cancers. Recent genome-scale studies in Drosophila melanogaster have revealed an extraordinarily complex network of genes that can affect Notch activity. This highly interconnected network contrasts our traditional view of the Notch pathway as a simple linear sequence of events. Although we now have an unprecedented insight into the way in which such a fundamental signalling mechanism is controlled by the genome, we are faced with serious challenges in analysing the underlying molecular mechanisms of Notch signal control.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                28 October 2017
                November 2017
                : 18
                : 11
                : 2272
                Affiliations
                [1 ]Department of Biomedical & Pharmaceutical Sciences, Chapman University, Irvine, CA 92618, USA; rrpala@ 123456chapman.edu (R.P.); aloma112@ 123456mail.chapman.edu (N.A.)
                [2 ]Harry and Diane Rinker Health Science Campus, Chapman University, 9401 Jeronimo Road, Irvine, CA 92618-1908, USA
                [3 ]Department of Medicine, University of California Irvine, Irvine, CA 92868, USA
                Author notes
                [* ]Correspondence: nauli@ 123456chapman.edu or snauli@ 123456uci.edu ; Tel.: +1-714-516-5480; Fax: +1-714-516-5481
                Article
                ijms-18-02272
                10.3390/ijms18112272
                5713242
                29143784
                76a170a6-3d02-4645-b061-3a71b5d09373
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 September 2017
                : 25 October 2017
                Categories
                Review

                Molecular biology
                calcium,cilioplasm,cytoplasm,sensory function,signaling
                Molecular biology
                calcium, cilioplasm, cytoplasm, sensory function, signaling

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