Microtubule Motors Drive Hedgehog Signaling in Primary Cilia

He, Mu; Agbu, Stephanie; Anderson, Kathryn V.

doi:10.1016/j.tcb.2016.09.010

Cited by 73 publications

(71 citation statements)

References 154 publications

(166 reference statements)

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“…[1][2][3][4][5][6][7] Therefore, the dysregulation of primary cilia can cause various diseases, including congenital anomalies, neurodevelopmental disorders, obesity, and cancer. Primary cilia detect extracellular cues, such as mechanical flow and chemical stimulation, and transduce these signals into the cell.…”

Section: Introductionmentioning

confidence: 99%

Primary Cilia as Signaling Hubs in Health and Disease

et al. 2018

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Primary cilia detect extracellular cues and transduce these signals into cells to regulate proliferation, migration, and differentiation. Here, the function of primary cilia as signaling hubs of growth factors and morphogens is in focus. First, the molecular mechanisms regulating the assembly and disassembly of primary cilia are described. Then, the role of primary cilia in mediating growth factor and morphogen signaling to maintain human health and the potential mechanisms by which defects in these pathways contribute to human diseases, such as ciliopathy, obesity, and cancer are described. Furthermore, a novel signaling pathway by which certain growth factors stimulate cell proliferation through suppression of ciliogenesis is also described, suggesting novel therapeutic targets in cancer.

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Section: Introductionmentioning

confidence: 99%

Primary Cilia as Signaling Hubs in Health and Disease

et al. 2018

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“…One well-studied example of ciliary signaling is the vertebrate Hedgehog (Hh) pathway [19,20] (Figure 1). Upon stimulation with Hh ligand, Patched is inhibited from localizing to the cilium [21,22].…”

Section: Introductionmentioning

confidence: 99%

“…Smoothened then accumulates in the cilium and inhibits SUFU, which stimulates the release of GLI from the cilium [23][24][25]. GLI is no longer processed by the proteasome and PKA into an inhibitor, instead acting as a transcriptional activator upon Hh stimulation [19,20,26]. The cilium therefore facilitates the spatial separation of pathway components, promoting a rapid, regulated response not requiring translation or long-distance protein 84 Cell organelles transport [17].…”

Section: Introductionmentioning

confidence: 99%

Gates for soluble and membrane proteins, and two trafficking systems (IFT and LIFT), establish a dynamic ciliary signaling compartment

Jensen

Leroux

2017

Current Opinion in Cell Biology

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“…Kinesins constitute a superfamily of microtubule-based molecular motor enzymes that couple the chemical energy from ATP turnover to force production for diverse cellular functions (reviewed in (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)). Kinesins are classified into 15 different subfamilies, yet they share a structurally conserved kinesin motor domain (1,3,(13)(14)(15)(16).…”

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confidence: 99%

Kinesin-2 motors: Kinetics and biophysics

Gilbert

Guzik-Lendrum

Rayment

2018

Journal of Biological Chemistry

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Kinesin-2s are major transporters of cellular cargoes. This subfamily contains both homodimeric kinesins whose catalytic domains result from the same gene product and heterodimeric kinesins with motor domains derived from two different gene products. In this review, we focus on the progress to define the biochemical and biophysical properties of the kinesin-2 family members. Our understanding of their mechanochemical capabilities has been advanced by the ability to identify the kinesin-2 genes in multiple species, expression and purification of these motors for single molecule and ensemble assays, and development of new technologies enabling quantitative measurements of kinesin activity with greater sensitivity.Kinesins constitute a superfamily of microtubule-based molecular motor enzymes that couple the chemical energy from ATP turnover to force production for diverse cellular functions (reviewed in (1-12)). Kinesins are classified into 15 different subfamilies, yet they share a structurally conserved kinesin motor domain (1,3,(13)(14)(15)(16). However, key amino acid residue changes can confer unique mechanochemical properties to each kinesin, which in turn specify cellular function. The N-terminal kinesins are composed of an N-terminal motor domain connected to a long a-helical region that dimerizes into a coiled-coil stalk that ends with a C-terminal domain that may interact with specific adaptor proteins for cargo linkage (Fig. 1). N-kinesin subfamilies include conventional kinesin-1, kinesin-2, kinesin-3, kinesin-5 Eg5/KSP, and kinesin-7 CENP-E, and all are best known for their roles in intracellular transport.N-kinesins carry cargo directionally toward the plus-end of microtubules, which are polymerized from ab-tubulin subunits to form a cylindrical polymer of 13 protofilaments. The kinesins are able to "read" the polarity of the microtubule because of the structural asymmetry of ab-tubulin subunits. The movement of N-kinesins is designated as "processive," which implies that upon microtubule collision, a single, dimeric kinesin steps continuously toward the microtubule plus end in an asymmetric hand-over-hand manner hydrolyzing one ATP per 8-nm step for hundreds of steps (17)(18)(19)(20)(21)(22). The 8-nm step size results from the distance between adjacent ab-tubulin dimers along the microtubule lattice. As Fig. 2 illustrates, a processive kinesin binds the microtubule and then goes through a series of structural transitions, each modulated by nucleotide state. To maintain a processive run with continuous stepping, the Kinesin-2 Molecular Motors 2ATPase cycle of each head remains out-of-phase with the other to avoid premature release if both heads exist in a microtubule weak binding state simultaneously. The degree of processivity, quantified by "run length," varies between kinesin subfamilies and is regulated by a series of "gating" mechanisms in which a chemical and/or mechanical requirement must be satisfied to proceed forward. There has been significant effort to define the determinants of ...

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Microtubule Motors Drive Hedgehog Signaling in Primary Cilia

Cited by 73 publications

References 154 publications

Primary Cilia as Signaling Hubs in Health and Disease

Primary Cilia as Signaling Hubs in Health and Disease

Gates for soluble and membrane proteins, and two trafficking systems (IFT and LIFT), establish a dynamic ciliary signaling compartment

Kinesin-2 motors: Kinetics and biophysics

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