Membrane‐bound Kit ligand regulates melanocyte adhesion and survival, providing physical interaction with an intraepithelial niche

Tabone‐Eglinger, Séverine; Wehrle-Haller, Monique; Aebischer, Nicole; Jacquier, Marie-Claude; Wehrle-Haller, Bernhard

doi:10.1096/fj.12-206045

Cited by 22 publications

(32 citation statements)

References 72 publications

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“…Interestingly, MMP‐9‐induced cleavage of mb‐KitL into s‐KitL correlated with the release of HSCs from bone marrow and their recruitment into the circulation (15), suggesting that mb‐KitL anchors HSCs to their niche. A similar anchorage and survival function of mb‐KitL has also been observed for melanoblasts residing in an epithelial niche (16). In addition to the critical role of KitL/c‐kit for HSC recruitment and binding to the bone marrow niche (17), cell surface receptors of the integrin family are also playing a critical function in c‐kit‐mediated migration and adhesion (18).…”

supporting

confidence: 67%

Niche anchorage and signaling through membrane‐bound Kit‐ligand/c‐kit receptor are kinase independent and imatinib insensitive

Tabone‐Eglinger¹,

Calderin-Sollet²,

Pinon³

et al. 2014

FASEB j.

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Kit ligand (KitL) and its tyrosine kinase receptor c-kit are critical for germ cells, melanocytes, mastocytes, and hematopoietic stem cells. Alternative splicing of KitL generates membrane-bound KitL (mb-KitL) or soluble KitL, providing survival or cell migration, respectively. Here we analyzed whether c-kit can function both as an adhesion and signaling receptor to mb-KitL presented by the environmental niche. At contacts between fibroblasts and MC/9 mast cells, mb-KitL, and c-kit formed ligand/receptor clusters that formed stable complexes, which resisted dissociation by c-kit blocking mAbs and provided cell anchorage under physiological shear stresses. Clusters recruited tyrosine-phosphorylated proteins and induced spatially restricted F-actin polymerization. Mutational analysis of c-kit demonstrated kinase-independent mb-KitL/c-kit clustering, anchorage, F-actin polymerization, and Tyr567-dependent cluster phosphorylation. Kinase inhibition of c-kit by imatinib reduced cluster coalescence, but allowed cluster phosphorylation and F-actin polymerization, which required PI3K recruitment and a newly identified juxtamembrane residue. Synergies between integrin and c-kit-mediated spreading and adhesion of MC/9 cells were studied in vitro on immobilized-KitL/fibronectin surfaces. While c-kit blocking antibodies prevented spreading, imatinib blocked spreading induced by soluble- but not immobilized KitL. Thus, "mechanical" activation of c-kit provides signaling, niche-anchorage, and synergies with integrin-mediated adhesion, which is independent of kinase function and resistant to c-kit kinase inhibitors.-

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supporting

confidence: 67%

Niche anchorage and signaling through membrane‐bound Kit‐ligand/c‐kit receptor are kinase independent and imatinib insensitive

Tabone‐Eglinger¹,

Calderin-Sollet²,

Pinon³

et al. 2014

FASEB j.

Self Cite

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“…MITF controls the expression of key pigment synthetic genes including TRP-1, DCT, and tyrosinase [32] . Various extracelluar signaling pathways converge on MITF to control both migration and survival of melanoblasts [35–40] .…”

Section: Introductionmentioning

confidence: 99%

Melanocyte stem cells as potential therapeutics in skin disorders

Lee

Fisher

2014

Expert Opinion on Biological Therapy

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Introduction Melanocytes produce pigment granules that color both skin and hair. In the hair follicles melanocytes are derived from stem cells (MelSC) that are present in hair bulges or sub-bulge regions and function as melanocyte reservoirs. Quiescence, maintenance, activation, and proliferation of MelSC are controlled by specific activities in the microenvironment that can influence the differentiation and regeneration of melanocytes. Therefore, understanding MelSC and their niche may lead to use of MelSC in new treatments for various pigmentation disorders. Areas covered We describe here pathophysiological mechanisms by which melanocyte defects lead to skin pigmentation disorders such as vitiligo and hair graying. The development, migration, and proliferation of melanocytes and factors involved in the survival, maintenance, and regeneration of MelSC are reviewed with regard to the biological roles and potential therapeutic applications in skin pigmentation diseases. Expert Opinion MelSC biology and niche factors have been studied mainly in murine experimental models. Human MelSC markers or methods to isolate them are much less well understood. Identification, isolation and culturing of human MelSC would represent a major step toward new biological therapeutic options for patients with recalcitrant pigmentary disorders or hair graying. By modulating the niche factors for MelSC it may one day be possible to control skin pigmentary disorders and prevent or reverse hair graying.

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“…A detailed protocol regarding melanocyte extraction can be found in the Methods section. The tdTomato mice were sacrificed, their skin harvested, and dermal cells sorted based on fluorescence of both tdTomato and FITC-labelled antibodies tagging c-Kit, a surface marker9. ZsGreen-labelled mice underwent a similar procedure, with melanocytes selected via their ZsGreen and c-Kit signals.…”

Section: Resultsmentioning

confidence: 99%

In vivo coherent Raman imaging of the melanomagenesis-associated pigment pheomelanin

Wang

Osseiran

Igras

et al. 2016

Sci Rep

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Melanoma is the most deadly form of skin cancer with a yearly global incidence over 232,000 patients. Individuals with fair skin and red hair exhibit the highest risk for developing melanoma, with evidence suggesting the red/blond pigment known as pheomelanin may elevate melanoma risk through both UV radiation-dependent and -independent mechanisms. Although the ability to identify, characterize, and monitor pheomelanin within skin is vital for improving our understanding of the underlying biology of these lesions, no tools exist for real-time, in vivo detection of the pigment. Here we show that the distribution of pheomelanin in cells and tissues can be visually characterized non-destructively and noninvasively in vivo with coherent anti-Stokes Raman scattering (CARS) microscopy, a label-free vibrational imaging technique. We validated our CARS imaging strategy in vitro to in vivo with synthetic pheomelanin, isolated melanocytes, and the Mc1re/e, red-haired mouse model. Nests of pheomelanotic melanocytes were observed in the red-haired animals, but not in the genetically matched Mc1re/e; Tyrc/c (“albino-red-haired”) mice. Importantly, samples from human amelanotic melanomas subjected to CARS imaging exhibited strong pheomelanotic signals. This is the first time, to our knowledge, that pheomelanin has been visualized and spatially localized in melanocytes, skin, and human amelanotic melanomas.

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Membrane‐bound Kit ligand regulates melanocyte adhesion and survival, providing physical interaction with an intraepithelial niche

Cited by 22 publications

References 72 publications

Niche anchorage and signaling through membrane‐bound Kit‐ligand/c‐kit receptor are kinase independent and imatinib insensitive

Niche anchorage and signaling through membrane‐bound Kit‐ligand/c‐kit receptor are kinase independent and imatinib insensitive

Melanocyte stem cells as potential therapeutics in skin disorders

In vivo coherent Raman imaging of the melanomagenesis-associated pigment pheomelanin

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