Loss of SPRY2 and activation of receptor tyrosine kinases are common events in prostate cancer (PC). However, the molecular basis of their interaction and clinical impact remains to be fully examined. SPRY2 loss may functionally synergize with aberrant cellular signalling to drive PC and to promote treatment-resistant disease. Here, we report evidence for a positive feedback regulation of the ErbB-PI3K/AKT cascade by SPRY2 loss in in vitro as well as pre-clinical in vivo models and clinical PC. Reduction in SPRY2 expression resulted in hyper-activation of PI3K/AKT signalling to drive proliferation and invasion by enhanced internalization of EGFR/HER2 and their sustained signalling at the early endosome in a PTEN-dependent manner. This involved p38 MAPK activation by PI3K to facilitate clathrin-mediated ErbB receptor endocytosis. Finally, in vitro and in vivo inhibition of PI3K suppressed proliferation and invasion, supporting PI3K/AKT as a target for therapy particularly in patients with PTEN-haploinsufficient-, low SPRY2- and ErbB-expressing tumours. In conclusion, SPRY2 is an important tumour suppressor in PC since its loss drives the PI3K/AKT pathway via functional interaction with the ErbB system.
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http://dx.doi.org/10.1002/emmm.201100944 | DOI Listing |
Skin Res Technol
September 2024
Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Jiangsu Engineering Research Center for Tumor Immunotherapy, Institute of Cell Therapy, Soochow University, Changzhou, Jiangsu, P. R. China.
Background: The malignancy of melanoma is attributed to its pronounced invasiveness, extensive vascularization, and rapid tumor cell growth and metastasis. LncRNA SLNCR1 is closely associated with a variety of aggressive tumors. However, our understanding of SLNCR1 influences on malignant melanoma growth metastasis mechanism especially proangiogenic mechanism remains unclear.
View Article and Find Full Text PDFSci Rep
August 2024
Developmental and Oncogenic Signaling Group, Edifici Biomedicina I, Lab 2.8, Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Rovira Roure, 80, 25198, Lleida, Spain.
Stromal fibroblasts are a major stem cell niche component essential for organ formation and cancer development. Fibroblast heterogeneity, as revealed by recent advances in single-cell techniques, has raised important questions about the origin, differentiation, and function of fibroblast subtypes. In this study, we show in mammary stromal fibroblasts that loss of the receptor tyrosine kinase (RTK) negative feedback regulators encoded by Spry1, Spry2, and Spry4 causes upregulation of signaling in multiple RTK pathways and increased extracellular matrix remodeling, resulting in accelerated epithelial branching.
View Article and Find Full Text PDFBreast Cancer Res
July 2023
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People's Republic of China.
The communication between tumor cells and tumor microenvironment plays a critical role in cancer development. Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment and take part in breast cancer formation and progression. Here, by comparing the gene expression patterns in CAFs and normal fibroblasts, we found SPRY2 expression was significantly decreased in CAFs and decreased SPRY2 expression was correlated with worse prognosis in breast cancer patients.
View Article and Find Full Text PDFCell Mol Gastroenterol Hepatol
March 2023
Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Biochemistry and Molecular Medicine, University of Southern California Keck School of Medicine, Los Angeles, California. Electronic address:
Background & Aims: Deep crypt secretory (DCS) cells are a critical component of the colonic stem cell niche. However, the regulatory mechanisms controlling DCS cell numbers and function are not well understood. Sprouty2 is an inflammation-responsive regulator of intracellular signaling that influences colonic secretory cell numbers in colitis via an epithelial-stromal interleukin (IL)33/IL13 signaling loop.
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