Intersectin-1s deficiency in pulmonary pathogenesis.
Niranjan Jeganathan1, Dan Predescu2, Sanda Predescu3
1Rush University Medical Center, Chicago, IL, 60612, USA. Niranjan_Jeganathan@Rush.edu.
Respiratory Research
|September 7, 2017
Summary
Intersectin-1s (ITSN-1s) deficiency is implicated in lung cancer and acute lung injury by affecting cell signaling and endocytosis. Its deficiency also drives pulmonary artery hypertension pathogenesis via protein fragments.
Area of Science:
- Pulmonary Pathology
- Cell Biology
- Molecular Mechanisms
Background:
- Intersectin-1s (ITSN-1s) is a multidomain adaptor protein crucial for endocytosis, cytoskeleton rearrangement, and cell signaling.
- ITSN-1s deficiency is an early event in pulmonary pathogenesis, impacting lung cancer and acute lung injury.
- ITSN-1s plays a role in inflammatory conditions like pulmonary artery hypertension.
Purpose of the Study:
- To elucidate the role of ITSN-1s in lung cancer, acute lung injury, and pulmonary artery hypertension.
- To investigate the molecular mechanisms by which ITSN-1s deficiency affects pulmonary pathology.
- To explore the potential of ITSN-1s as a therapeutic target for pulmonary diseases.
Main Methods:
- Analysis of ITSN-1s deficiency in lung cancer cell proliferation, migration, and metastasis.
- Investigation of ITSN-1s role in endocytosis and growth factor receptor degradation in acute lung injury.
- Study of ITSN-1s cleavage by granzyme B and the role of its fragments in pulmonary artery hypertension.
- Utilizing genetically modified ITSN-1s expression mouse models.
Main Results:
- ITSN-1s deficiency in lung cancer enhances proliferation and metastasis by altering Eps8 ubiquitination and Rac1 activation.
- In acute lung injury, ITSN-1s deficiency impairs endocytosis, leading to growth factor receptor degradation, with microparticles partially restoring function.
- ITSN-1s cleavage in pulmonary artery hypertension generates fragments that promote pulmonary cell proliferation and vascular pathology.
- ITSN-1s deficient mice with EHITSN expression exhibit pulmonary vascular obliteration and plexiform lesions.
Conclusions:
- ITSN-1s deficiency significantly contributes to the pathogenesis of lung cancer, acute lung injury, and pulmonary artery hypertension.
- Understanding ITSN-1s's multifaceted roles provides insights into pulmonary disease mechanisms.
- Genetically modified ITSN-1s mouse models are valuable tools for studying pulmonary pathology and identifying therapeutic targets.
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