Abstract
Understanding the fundamental role of the stroma in normal development and cancer progression has been an emerging focus in recent years. The receptor tyrosine kinase (RTK) signaling pathway has been reported playing critical roles in regulating the normal and cancer microenvironment, but the underlying mechanism is still not very clear. By applying the quantitative phosphoproteomic analysis of Sprouty proteins (SPRYs), generic modulators of RTK signaling and deleted mouse mammary fibroblasts, we quantified a total of 11,215 unique phosphorylation sites. By contrast, 554 phosphorylation sites on 425 proteins had SPRY-responsive perturbations. Of these, 554 phosphosites, 362 sites on 277 proteins, were significantly increased, whereas 192 sites on 167 proteins were decreased. Among the regulated proteins, we identified 31 kinases, 7 phosphatases, and one phosphatase inhibitor that were not systematically characterized before. Furthermore, we reconstructed a phosphorylation network centered on RTK signaling regulated by SPRY. Collectively, this study uncovered a system-wide phosphorylation network regulated by SPRY, providing an additional insight into the complicated RTK signaling pathways involved in the mammary gland microenvironment.
Highlights
The local microenvironment is essential in regulating cell polarity, migration, cell differentiation and tumor progression [1,2,3]
Previous studies have reported that Sprouty proteins (SPRYs) proteins function as both negative and positive regulators of Ras, extracellular signal–regulated kinase (ERK) and mitogen-activated protein kinase (MAPK) signaling pathways that are downstream of several receptor tyrosine kinase (RTK) signaling (FGF, epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF)) pathways in a cell type-dependent manner (Table 1)
Sprouty (Spry) family genes Sprouty protein 1 (Spry1), Spry2 and Spry4 are differentially expressed in breast cancer, but Spry3 is rarely expressed [22,23]
Summary
The local microenvironment is essential in regulating cell polarity, migration, cell differentiation and tumor progression [1,2,3]. Previous studies have reported that SPRY proteins function as both negative and positive regulators of Ras, extracellular signal–regulated kinase (ERK) and mitogen-activated protein kinase (MAPK) signaling pathways that are downstream of several RTK signaling (FGF, epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF)) pathways in a cell type-dependent manner (Table 1). Our previous study revealed that SPRY1 inhibits the epidermal growth factor receptor (EGFR)-dependent stromal paracrine signaling pathway and ECM remodeling, by decreasing ERK signaling activity in mammary stromal fibroblasts. In the study, overexpression of Spry in mammary stroma has contrary phenotypes compared with Spry loss [6] This data indicates that similar to the SPRY function in other cellular contexts [16,17,18,19], SPRY family proteins may play redundant roles in the mammary stromal fibroblasts. Data were collected from the National Center for Biotechnology Information (NCBI) Database, the UniProt database, and the GeneCards Database
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