Ciliary control of adipocyte progenitor cell fate regulates energy storage

Scamfer, Sierra R.; Lee, Mark D.; Hilgendorf, Keren I.

doi:10.3389/fcell.2022.1083372

Cited by 8 publications

(4 citation statements)

References 152 publications

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“…On a molecular level, upon activation of receptors in the cilium, second messengers, such as calcium and cAMP, are utilized to either directly modify downstream signal mediators or evoke signaling through posttranslational modifications (PTMs) (May et al , 2021b ) (Fig 1B ). This concept mainly holds true for GPCRs (Schou et al , 2015 ; Hilgendorf et al , 2016 ; Mykytyn & Askwith, 2017 ; Garcia et al , 2018 ; Wachten & Mick, 2021 ; Scamfer et al , 2022 ). Other ciliary chemoreceptors, such as Receptor Tyrosine Kinases (RTKs) and Transforming Growth Factor beta (TGFβ) receptors, directly phosphorylate their targets to change ciliary signaling dynamics and evoke a downstream cellular response (Christensen et al , 2017 ).…”

Section: The Different Levels Of Primary Cilia Dynamicsmentioning

confidence: 99%

Emerging principles of primary cilia dynamics in controlling tissue organization and function

Gopalakrishnan,

Feistel,

Friedrich

et al. 2023

The EMBO Journal

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Primary cilia project from the surface of most vertebrate cells and are key in sensing extracellular signals and locally transducing this information into a cellular response. Recent findings show that primary cilia are not merely static organelles with a distinct lipid and protein composition. Instead, the function of primary cilia relies on the dynamic composition of molecules within the cilium, the context‐dependent sensing and processing of extracellular stimuli, and cycles of assembly and disassembly in a cell‐ and tissue‐specific manner. Thereby, primary cilia dynamically integrate different cellular inputs and control cell fate and function during tissue development. Here, we review the recently emerging concept of primary cilia dynamics in tissue development, organization, remodeling, and function.

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Section: The Different Levels Of Primary Cilia Dynamicsmentioning

confidence: 99%

Emerging principles of primary cilia dynamics in controlling tissue organization and function

Gopalakrishnan,

Feistel,

Friedrich

et al. 2023

The EMBO Journal

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“…It seems unlikely, however, that the pool of GRK2 at the base of the cilium is singularly dedicated to serving the needs of SMO during Hh signal transduction. Indeed, the cilium is home to a host of GPCRs critical to the nervous, cardiovascular, and musculoskeletal systems, and dysregulation of these receptors is associated with a range of devastating pathologies 9,10,125 . Many of these GPCRs are assumed to undergo agonist-dependent GRK phosphorylation in the cilium, but to our knowledge, this has never been demonstrated directly.…”

Section: Grk Control Of Gpcr Signaling In the Cilium And Beyondmentioning

confidence: 99%

GRK2 Kinases in the Primary Cilium Initiate SMOOTHENED-PKA Signaling in the Hedgehog Cascade

Walker

Zhang

Steiner

et al. 2023

Preprint

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During Hedgehog (Hh) signal transduction in development, homeostasis, and cancer, the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO) communicates with GLI transcription factors by directly binding the PKA catalytic subunit (PKA-C) and physically blocking its enzymatic activity. Here we show that GPCR kinase 2 (GRK2) orchestrates this process during endogenous Hh signal transduction in the vertebrate primary cilium. Hh pathway activation triggers rapid GRK2 relocalization from the base to the shaft of the cilium, leading to SMO phosphorylation and ultimately formation of SMO / PKA-C complexes in this compartment. In vitro reconstitution experiments reveal that GRK2 phosphorylation is sufficient to trigger direct binding of the SMO active conformation to PKA-C, without participation from additional proteins. Lastly, the SMO-GRK2-PKA communication pathway operates during Hh signaling in a range of cellular and in vivo models. Our work highlights GRK2 phosphorylation of ciliary SMO as a key initiating event for the intracellular steps of the Hh cascade, enabling a deeper understanding of how Hh signals are transduced intracellularly in tissues and organs to orchestrate proliferative and differentiative decisions. More broadly, our study hints at an expanded role for GRKs in enabling direct GPCR interactions with a diverse array of intracellular effectors.

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“…Cilia could be regarded as a downstream target of FSTL1 and thus understanding how FSTL1 regulates cilia is critical to dissect its function both in homeostatic and pathological conditions. For example, the primary cilium and ciliary proteins have been shown to be regulators of adipogenesis (reviewed in [24]). During adipocyte differentiation cilia show a similar pattern compared to FSTL1: cilia are present in pre-adipocytes but are reabsorbed as differentiation proceeds [13, 25].…”

Section: Introductionmentioning

confidence: 99%

FSTL1 is an antagonist of ERK1/2 phosphorylation during ciliogenesis and preadipocyte differentiation

Santos,

Guggeri,

Escande

et al. 2024

Preprint

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FSTL1 is a secreted glycoprotein that is involved in several processes in health and disease, including development, cardiovascular disease, cancer, inflammation, and obesity. The signaling pathways used by FSTL1 to act on target tissues seem to activate different intracellular mediators specific to each tissue and several of the mechanisms of action remain to be determined at the molecular level, including intracellular mediators and receptors. We have previously unveiled a novel role for FSTL1 in ciliogenesis and provided evidence for an Fstl1/cilia axis in preadipocyte differentiation. This pathway is relevant to the pathogenesis of obesity and of a group of conditions called ciliopathies since they are caused by the dysfunction of the primary cilia. This work aimed to identify intracellular mediators of FSTL1 action on ciliogenesis and adipogenesis. We analyzed ERK phosphorylation levels as well as cilia length in the absence of FSTL1 and in the presence of the pERK inhibitor U0126. We also analyzed the differentiation and cilia dynamics of U0126-treated preadipocytes and tested the ERK-mediated signaling by BMP4 in the presence of added extracellular Fstl1. Here, we propose that MAP kinase ERK is a mediator of ciliogenesis downstream of FSTL1 and provide additional data that suggest that FSTL1 antagonizes BMP non-canonical signaling to modulate ciliogenesis and adipogenesis. In sum, our data reinforce the interest on the axis FSTL1/cilia in the modulation of adipogenesis and provide evidence to add ERK to this working model.

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Ciliary control of adipocyte progenitor cell fate regulates energy storage

Cited by 8 publications

References 152 publications

Emerging principles of primary cilia dynamics in controlling tissue organization and function

Emerging principles of primary cilia dynamics in controlling tissue organization and function

GRK2 Kinases in the Primary Cilium Initiate SMOOTHENED-PKA Signaling in the Hedgehog Cascade

FSTL1 is an antagonist of ERK1/2 phosphorylation during ciliogenesis and preadipocyte differentiation

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