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Lung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation.

ABSTRACT: Lung mast cells are important in host defense, and excessive proliferation or activation of these cells can cause chronic inflammatory disorders like asthma. Two parallel pathways induced by KIT-stem cell factor (SCF) and FcεRI-immunoglobulin E interactions are critical for the proliferation and activation of mast cells, respectively. Here, we report that mast cell-expressed membrane protein1 (MCEMP1), a lung-specific surface protein, functions as an adaptor for KIT, which promotes SCF-mediated mast cell proliferation. MCEMP1 elicits intracellular signaling through its cytoplasmic immunoreceptor tyrosine-based activation motif and forms a complex with KIT to enhance its autophosphorylation and activation. Consequently, MCEMP1 deficiency impairs SCF-induced peritoneal mast cell proliferation in vitro and lung mast cell expansion in vivo. Mcemp1-deficient mice exhibit reduced airway inflammation and lung impairment in chronic asthma mouse models. This study shows lung-specific MCEMP1 as an adaptor for KIT to facilitate SCF-mediated mast cell proliferation.

SUBMITTER: Choi YJ

PROVIDER: S-EPMC10090139 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Lung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation.

Choi Youn Jung YJ Yoo Ji-Seung JS Jung Kyle K Rice Logan L Kim Dokyun D Zlojutro Violetta V Frimel Matthew M Madden Evan E Choi Un Yung UY Foo Suan-Sin SS Choi Younho Y Jiang Zhongyi Z Johnson Holly H Kwak Mi-Jeong MJ Kang Seokmin S Hong Brian B Seo Gil Ju GJ Kim Stephanie S Lee Shin-Ae SA Amini-Bavil-Olyaee Samad S Maazi Hadi H Akbari Omid O Asosingh Kewal K Jung Jae U JU

Nature communications 20230411 1

Lung mast cells are important in host defense, and excessive proliferation or activation of these cells can cause chronic inflammatory disorders like asthma. Two parallel pathways induced by KIT-stem cell factor (SCF) and FcεRI-immunoglobulin E interactions are critical for the proliferation and activation of mast cells, respectively. Here, we report that mast cell-expressed membrane protein1 (MCEMP1), a lung-specific surface protein, functions as an adaptor for KIT, which promotes SCF-mediated ...[more]

PMID: 37041174

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Project description:IntroductionBreast cancer remains the second leading cause of cancer-related deaths for women in the United States. Metastasis is regulated not only by intrinsic genetic changes in malignant cells, but also by the microenvironment, especially those associated with chronic inflammation. We recently reported that mice with autoimmune arthritis have significantly increased incidence of bone and lung metastasis and decreased survival associated with breast cancer. In this study, we evaluated the mechanism underlying the increased metastasis.MethodsWe used two mouse models; one that develops spontaneous autoimmune arthritis (SKG mice) injected with metastatic breast cancer cells (4T1), and another that develops spontaneous breast cancer (MMTV-PyV MT mice) injected with type II collagen to induce autoimmune arthritis. Mast cell levels and metastasis were monitored.ResultsFirst, we confirmed that breast tumor-bearing arthritic mice have a significantly higher incidence of bone and lung metastasis than do their nonarthritic counterparts. Next, we showed increased recruitment of mast cells within the primary tumor of arthritic mice, which facilitates metastasis. Next, we report that arthritic mice without any tumors have higher numbers of mast cells in the bones and lungs, which may be the underlying cause for the enhanced lung and bone metastases observed in the arthritic mice. Next, we showed that once the tumor cells populate the metastatic niches (bones and lungs), they further increase the mast cell population within the niche and assist in enhancing metastasis. This may primarily be due to the interaction of c-Kit receptor present on mast cells and stem cell factor (SCF, the ligand for ckit) expressed on tumor cells. Finally, we showed that targeting the SCF/cKit interaction with an anti-ckit antibody reduces the differentiation of mast cells and consequently reduces metastasis.ConclusionThis is the first report to show that mast cells may play a critical role in remodeling not only the tumor microenvironment but also the metastatic niche to facilitate efficient metastasis through SCF/cKit interaction in breast cancer with arthritis.

Dataset Information

Lung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation.

Publications

Lung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation.

Similar Datasets

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