MTZ®-MPI-Award 2022 to Nida Arif

On November 18, 2022, the MTZ®foundation will honor Nida Arif. She has published a significant paper in the department of Dietmar Vestweber at the Max Planck Institute (MPI) for Molecular Biomedicine, in which she reveals the molecular mechanism for destabilization of endothelial junctions. This is required for the extravasation of leukocytes during the immune response.
Since 2009, the MTZ®foundation annually honors young scientists at the MPI for Molecular Biomedicine with the MTZ®-MPI Award, which is endowed with 2,500 euros. In this way, the founding couple Monika and Thomas Zimmermann would like to support young people on their way into research.

How endothelial cell contacts open to allow the passage of leukocytes towards the site of infection

During inflammation or tissue injuries, our body generates an immune response to defend against foreign and harmful substances. This response allows immune cells such as leukocytes to cross the blood vessel wall and reach the site of infection in a process called diapedesis. Intact blood vessel walls are lined by endothelial cells. VE-cadherin is one of the major adhesion molecules of endothelial junctions, which maintains endothelial barrier integrity. Leukocyte diapedesis through the endothelium towards sites of infection is achieved by opening of VE-cadherin-based endothelial cell junctions. In her thesis, Nida Arif aimed to uncover the signaling pathways initiated in endothelial cells after adhesion of leukocytes, which result in the opening of junctions and allow the passage of leukocytes. Her work culminated in a scientific article published in EMBO Journal in February 2021.

One of the principal steps in leukocyte diapedesis is the destabilization of VE-cadherin-based junctions. The lab of Dietmar Vestweber has previously shown that the tyrosine residue Y731 in the cytoplasmic domain of VE-cadherin is the pivotal phosphorylation site that controls leukocyte diapedesis in response to inflammation. In resting endothelial cells, VE-cadherin is constitutively phosphorylated at Y731 and this site is physically protected by catenin binding to the same region of VE-cadherin. Under inflammatory conditions, leukocyte docking to the endothelium induces dephosphorylation of this tyrosine residue, which is catalyzed by the phosphatase SHP2 and is indispensable for leukocyte transmigration.
In the current work of Nida Arif, she revealed the underlying molecular mechanism that supports diapedesis. “We found that PECAM-1, a well-reported diapedesis-supporting adhesion molecule, delivers SHP2 to VE-cadherin, thus mediating direct dephosphorylation of Y731 and thereby promoting the subsequent endocytosis of VE-cadherin,” Nida says. The contribution of PECAM-1 to leukocyte diapedesis in vitro and in vivo is based on targeting VE-cadherin for destabilization of endothelial barrier.

“My results support a diapedesis model, in which leukocyte stimulation triggers an influx of calcium, which leads to actomyosin contraction in endothelial cells,” Nida explains. “This endothelial contractility generates pulling forces on the VE-cadherin-catenin complex, which might modulate the conformation of the complex in a way that renders catenin-masked Y731 exposed, thereby making it accessible for SHP2-mediated dephosphorylation.”

Further work shows that the adhesion of leukocytes to the endothelium leads to the dissociation of p120-catenin from VE-cadherin, which exposes an endocytic signal that results in the activation of the endocytic machinery, thus resulting in internalization of VE-cadherin and the opening of endothelial junctions to allow the passage of leukocytes towards the area of infection.

“My in-depth analysis of the molecular events in endothelial cells during leukocyte diapedesis unraveled the precise signaling mechanisms that culminate in endothelial junctional opening, allowing the movement of leukocytes from the blood vessels to the underlying tissue in order to fight infection,” Nida Arif concludes.

About Nida Arif

Nida Arif (31) completed her bachelor's degree as a topper in the Department of Biotechnology from Integral University, India. She was awarded a gold medal for the same. At the same time, she was presented with a silver medal for obtaining overall 2nd rank among the graduating students of the University. It was an astounding start, which motivated her to pursue her career in the field of Cell Biology.

During the second year of her Master’s studies at Indian Institute of Technology (IIT) Kharagpur, she was granted a DAAD Scholarship and earned the opportunity to do a research project under the IIT-DAAD student exchange program at the institute of Cell Biology and Immunology from the University of Stuttgart, Germany. Following seven months of research project, she got awarded with a silver medal for securing the 1st rank in her department at IIT-Kharagpur. 

Instantly after her Masters, she joined the CiM-IMPRS Graduate School for her PhD studies in Münster. She completed her PhD thesis under the supervision of Prof. Dr. Dietmar Vestweber at the Max Planck Institute for Molecular Biomedicine, which lead to her work being published in the EMBO Journal

Go to Editor View