Hedgehog-induced ciliary trafficking of kinesin-4 motor KIF7 requires intraflagellar transport but not KIF7’s microtubule binding

2021 ◽  
Author(s):  
Yang Yue ◽  
Martin F. Engelke ◽  
T. Lynne Blasius ◽  
Kristen J. Verhey
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Primary Cilium ◽  
Hedgehog Signaling ◽  
Intraflagellar Transport ◽  
Hedgehog Signaling Pathway ◽  
Microtubule Binding ◽  
Pathway Activation ◽  
Gli Transcription Factors ◽  
Ciliary Localization

The kinesin-4 motor KIF7 is a conserved regulator of the Hedgehog signaling pathway. In vertebrates, Hedgehog signaling requires the primary cilium, and KIF7 and Gli transcription factors accumulate at the cilium tip in response to Hedgehog activation. Unlike conventional kinesins, KIF7 is an immotile kinesin and its mechanism of ciliary accumulation is unknown. We generated KIF7 variants with altered microtubule binding or motility. We demonstrate that microtubule binding of KIF7 is not required for the increase in KIF7 or Gli localization at the cilium tip in response to Hedgehog signaling. In addition, we show that the immotile behavior of KIF7 is required to prevent ciliary localization of Gli transcription factors in the absence of Hedgehog signaling. Using an engineered kinesin-2 motor that enables acute inhibition of intraflagellar transport (IFT), we demonstrate that kinesin-2 KIF3A/KIF3B/KAP mediates the translocation of KIF7 to the cilium tip in response to Hedgehog pathway activation. Together, these results suggest that KIF7’s role at the tip of the cilium is unrelated to its ability to bind to microtubules.

scholarly journals The role of the Hedgehog signaling pathway in cancer: A comprehensive review

2018 ◽  
Vol 18 (1) ◽  
pp. 8-20 ◽  
Author(s):  
Ana Marija Skoda ◽  
Dora Simovic ◽  
Valentina Karin ◽  
Vedran Kardum ◽  
Semir Vranic ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Biological Effects ◽  
Signal Transmission ◽  
Adenosine Monophosphate ◽  
Evolutionary Pathway ◽  
Gli Transcription Factors ◽  
Hh Signaling

The Hedgehog (Hh) signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli) transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), Patched receptor (Ptch1, Ptch2), Smoothened receptor (Smo), Suppressor of fused homolog (Sufu), kinesin protein Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP). The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling) or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling – autocrine or paracrine). Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.

scholarly journals The Hedgehog Signaling Pathway in Idiopathic Pulmonary Fibrosis: Resurrection Time

2021 ◽  
Vol 23 (1) ◽  
pp. 171
Author(s):  
Wiwin Is Effendi ◽  
Tatsuya Nagano
Keyword(s):  
Transcription Factors ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Essential Role ◽  
Tissue Injury ◽  
Hedgehog Signaling Pathway ◽  
Cell Specification ◽  
Signal Activity

The hedgehog (Hh) pathway is a sophisticated conserved cell signaling pathway that plays an essential role in controlling cell specification and proliferation, survival factors, and tissue patterning formation during embryonic development. Hh signal activity does not entirely disappear after development and may be reactivated in adulthood within tissue-injury-associated diseases, including idiopathic pulmonary fibrosis (IPF). The dysregulation of Hh-associated activating transcription factors, genomic abnormalities, and microenvironments is a co-factor that induces the initiation and progression of IPF.

scholarly journals The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1188
Author(s):  
Jian Yi Chai ◽  
Vaisnevee Sugumar ◽  
Mohammed Abdullah Alshawsh ◽  
Won Fen Wong ◽  
Aditya Arya ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Clinical Settings ◽  
Developmental Studies ◽  
Holistic View ◽  
Gli Transcription Factors ◽  
Cancer Initiation ◽  
The Common

The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved among mammals, with crucial roles in regulating embryonic development as well as in cancer initiation and progression. The GLI transcription factors (GLI1, GLI2, and GLI3) are effectors of the Hh pathway and are regulated via Smoothened (SMO)-dependent and SMO-independent mechanisms. The SMO-dependent route involves the common Hh-PTCH-SMO axis, and mutations or transcriptional and epigenetic dysregulation at these levels lead to the constitutive activation of GLI transcription factors. Conversely, the SMO-independent route involves the SMO bypass regulation of GLI transcription factors by external signaling pathways and their interacting proteins or by epigenetic and transcriptional regulation of GLI transcription factors expression. Both routes of GLI activation, when dysregulated, have been heavily implicated in tumorigenesis of many known cancers, making them important targets for cancer treatment. Hence, this review describes the various SMO-dependent and SMO-independent routes of GLI regulation in the tumorigenesis of multiple cancers in order to provide a holistic view of the paradigms of hedgehog signaling networks involving GLI regulation. An in-depth understanding of the complex interplay between GLI and various signaling elements could help inspire new therapeutic breakthroughs for the treatment of Hh-GLI-dependent cancers in the future. Lastly, we have presented an up-to-date summary of the latest findings concerning the use of Hh inhibitors in clinical developmental studies and discussed the challenges, perspectives, and possible directions regarding the use of SMO/GLI inhibitors in clinical settings.

scholarly journals Intraflagellar transport is deeply integrated in hedgehog signaling

2018 ◽  
Vol 29 (10) ◽  
pp. 1178-1189 ◽  
Author(s):  
Thibaut Eguether ◽  
Fabrice P. Cordelieres ◽  
Gregory J. Pazour
Keyword(s):  
Transcription Factors ◽  
Membrane Protein ◽  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Intraflagellar Transport ◽  
Hedgehog Pathway ◽  
Gli Transcription Factors ◽  
Cilia Formation ◽  
Mutant Cells

The vertebrate hedgehog pathway is organized in primary cilia, and hedgehog components relocate into or out of cilia during signaling. Defects in intraflagellar transport (IFT) typically disrupt ciliary assembly and attenuate hedgehog signaling. Determining whether IFT drives the movement of hedgehog components is difficult due to the requirement of IFT for building cilia. Unlike most IFT proteins, IFT27 is dispensable for cilia formation but affects hedgehog signaling similarly to other IFTs, allowing us to examine its role in the dynamics of signaling. Activating signaling at points along the pathway in Ift27 mutant cells showed that IFT is extensively involved in the pathway. Similar analysis of Bbs mutant cells showed that BBS proteins participate at many levels of signaling but are not needed to concentrate Gli transcription factors at the ciliary tip. Our analysis showed that smoothened delivery to cilia does not require IFT27, but the role of other IFTs is not known. Using a rapamycin-induced dimerization system to sequester IFT-B proteins at the mitochondria in cells with fully formed cilia did not affect the delivery of Smo to cilia, suggesting that this membrane protein may not require IFT-B for delivery.

scholarly journals Assessment of Hedgehog Signaling Pathway Activation for Craniofacial Bone Regeneration in a Critical-Sized Rat Mandibular Defect

2019 ◽  
Vol 21 (2) ◽  
pp. 110-117 ◽  
Author(s):  
Matthew Q. Miller ◽  
Logan F. McColl ◽  
Michael R. Arul ◽  
Jonathan Nip ◽  
Vedavathi Madhu ◽  
...  
Keyword(s):  
Bone Regeneration ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Hedgehog Signaling Pathway ◽  
Craniofacial Bone ◽  
Pathway Activation ◽  
Mandibular Defect

Effect of Hedgehog Signaling Pathway Activation on Proliferation of High-Grade Gliomas

2016 ◽  
Vol 161 (5) ◽  
pp. 674-678 ◽  
Author(s):  
S. A. Cherepanov ◽  
K. I. Cherepanova ◽  
N. F. Grinenko ◽  
O. M. Antonova ◽  
V. P. Chekhonin
Keyword(s):  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Hedgehog Signaling Pathway ◽  
High Grade ◽  
Pathway Activation ◽  
High Grade Gliomas

Nuclear Factor-κB Contributes to Hedgehog Signaling Pathway Activation through Sonic Hedgehog Induction in Pancreatic Cancer

2006 ◽  
Vol 66 (14) ◽  
pp. 7041-7049 ◽  
Author(s):  
Hiroshi Nakashima ◽  
Masafumi Nakamura ◽  
Hiroshi Yamaguchi ◽  
Naoki Yamanaka ◽  
Takashi Akiyoshi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Nuclear Factor Κb ◽  
Hedgehog Signaling Pathway ◽  
Nuclear Factor ◽  
Pathway Activation

scholarly journals Secreted tyrosine kinase Vlk negatively regulates Hedgehog signaling by inducing lysosomal degradation of Smoothened

2020 ◽  
Vol 477 (1) ◽  
pp. 121-136
Author(s):  
June Myoung Kim ◽  
Hyeseung Han ◽  
Minjin Bahn ◽  
Yeokyu Hur ◽  
Chang-Yeol Yeo ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Skeletal Development ◽  
Hedgehog Pathway ◽  
Hedgehog Signaling Pathway ◽  
Signal Transducer ◽  
Lysosomal Degradation ◽  
Genetic Studies ◽  
Ciliary Localization

Vlk is a secreted tyrosine kinase that plays crucial roles during vertebrate embryonic development including skeletal formation. Genetic studies suggest that Vlk can modulate the Hedgehog signaling pathway during skeletal development. Despite its potential roles as an extracellular regulator of signaling pathways, little is known regarding the molecular functions of Vlk. Here we show that Vlk can negatively regulate the Hedgehog signaling pathway. We found that Vlk can induce lysosomal degradation of Smoothened, a crucial transmembrane signal transducer of the Hedgehog pathway, through the interaction with the extracellular domain of Smoothened (Smo-ECD). In addition, we observed that Vlk can attenuate Hedgehog signaling-induced ciliary localization of Smoothened. Furthermore, Vlk-mediated suppression of Hedgehog signaling can be diminished by tyrosine-to-phenylalanine substitutions in Smo-ECD. Taken together, these results suggest that Vlk may function as a signaling regulator in extracellular space to modulate the Hedgehog pathway.

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