Abstract P2-16-09: Dual Specific Phosphatase-7 (DUSP7/PYST2) and its role in regulating vascular endothelial functions

Abstract

Abstract Dual Specific Phosphatase-7 (DUSP7/PYST2) and its role in regulating vascular endothelial functions Wenxiao Ji, Wen G. Jiang, Lin Ye, Tracey A. Martin CCMRC, Cardiff University School of Medicine, Cardiff, Wales, UK Introduction. Dual specific phosphatases (DUSPs) are a large family of enzyme able to trigger tyrosine phosphorylation, and phosphorylation of serine and/or threonine. This feature of a dual phosphorylation pattern by DUSPs, renders them with diverse roles in cells, from cytoskeletal regulation of cell migration, regulation of multiple kinases in cell signalling, to regulation of proteins such as microtubules and cell growth. We have investigated DUSP family members, in particular DUSP-7 (otherwise known as PYST2), identified from our studies as being one of prominent DUSPs found to be highly aberrant in certain cancer types including gastric cancer and pancreatic cancer. In breast cancer cells, DUSP7 has been reported as a potential factor linked to drug sensitivity. The role played by DUSP7 in vascular endothelial cells has been poorly studied. Here, we present our findings on the role of DUSP-7 in the regulation of biological functions of vascular endothelial cells. Methods. Human vascular endothelial cells were used in the present study. Cell sub-models were created by knock down of DUSP7. The cells were evaluated for their biological response to loss of DUSP7, including proliferation, migration, matrix adhesion and response to downstream signalling. DUSP7 responses to various exogenous factors were also evaluated by a protein kinase platform. Results. Knock down of DUSP7 in human endothelial cells rendered them manifesting significantly reduced matrix adhesiveness (p< 0.05) and most strikingly, reduced cellular migration (P< 0.0001, control versus DUSP7 knock down). Interestingly, there was little change with the rate of cell growth. When cells were tested by inhibiting a tight junctional molecule, HAVcR1, the endothelial cells responded with markedly reduced DUSP7 (reduction of 46%). Likewise, the cells were also exhibited reduced levels of DUSP7 after being challenged by exogenous metastasis related Kisspeptin, indicating that DUSP7 may participated the wide network of signalling and functional regulations shared with the tight junction regulator HAVcR1 and possibly utilising Mitogen-activated protein kinase 3 (MAPK3 or Extracellular signal regulated kinase-1). Conclusion. Dual specific phosphatase-7 has an important role to play in vascular endothelial cells, primarily on cell matrix adhesion and cellular migration. A possible route of regulation is by targeting the extracellular signalling network. Citation Format: WENXIAO JI, Wen G. Jiang, Lin Ye, Tracey A. Martin. Dual Specific Phosphatase-7 (DUSP7/PYST2) and its role in regulating vascular endothelial functions [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-16-09.