%0 Journal Article
%T Human Sprouty1 Suppresses Urokinase Receptor-Stimulated Cell Migration and Invasion
%A Ahmed H. Mekkawy
%A David L. Morris
%J ISRN Biochemistry
%D 2013
%R 10.1155/2013/598251
%X The urokinase-type plasminogen activator receptor (uPAR) has been implicated in several processes in tumor progression including cell migration and invasion in addition to initiation of signal transduction. Since uPAR lacks a transmembrane domain, it uses the interaction with other proteins to modulate intracellular signal transduction. We have previously identified hSpry1 as a partner protein of uPAR, suggesting a physiological role for hSpry1 in the regulation of uPAR signal transduction. In this study, hSpry1 was found to colocalize with uPAR upon stimulation with epidermal growth factor (EGF), urokinase (uPA), or its amino terminal fragment (uPA-ATF), implicating a physiological role of hSpry1 in regulation of uPAR signalling pathway. Moreover, hSpry1 was able to inhibit uPAR-stimulated cell migration in HEK293/uPAR, breast carcinoma, and colorectal carcinoma cells. In addition, hSpry1 was found to inhibit uPAR-stimulated cell invasion in breast carcinoma and osteosarcoma cell lines. Increasing our understanding of how hSpry1 negatively regulates uPAR-stimulated cellular functions may determine a distinctive role for hSpry1 in tumour suppression. 1. Introduction The serine protease urokinase-type plasminogen activator (uPA) receptor (uPAR) has been implicated in extracellular matrix (ECM) proteolysis, initiation of signal transduction, and important cell functions including migration and invasion [1]. The active uPA consists of catalytic protease domain and the uPA amino terminal fragment (uPA-ATF) [2]. uPA-ATF contains the kringle domain and the growth factor-like domain (GFD) that contains the binding sequence for the receptor [2]. The uPAR protein has been shown to engage in multiple protein-protein interactions with other proteins such as vitronectin, integrins, and Mrj [3¨C5]. Sprouty (Spry) proteins have been identified as inhibitors of the receptor tyrosine kinase (RTK) including (epidermal growth factor receptor) EGFR [6]. The mammalian genome contains four SPRY genes (SPRY 1¨C4) encoding proteins with a conserved cysteine-rich region at the carboxyl terminus [7]. Due to its central role in Ras/MAP kinase pathway, SPRY may act as a putative tumor suppressor gene, and that loss of expression or function may allow the cell to be hypersensitive to growth signals [8]. Interestingly, the tumor suppressor gene, WT1, has been found to bind with SPRY1 promoter and regulate it during kidney development [9]. Prostate ductal hyperplasia and low-grade prostatic intraepithelial neoplasia (PIN) have been observed in adult mouse with concomitant Spry1 and
%U http://www.hindawi.com/journals/isrn.biochemistry/2013/598251/