title: Cosuppression of Sprouty and Sprouty-related negative regulators of FGF signalling in prostate cancer: a working hypothesis.
abstract: Deregulation of FGF receptor tyrosine kinase (RTK) signalling is common in prostate cancer. Normally, to moderate RTK signalling, induction of Sprouty (SPRY) and Sprouty-related (SPRED) antagonists occurs. Whilst decreased SPRY and SPRED has been described in some cancers, their role in prostate cancer is poorly understood. Therefore, we hypothesise that due to the need for tight regulation of RTK signalling, SPRY and SPRED negative regulators provide a degree of redundancy which ensures that a suppression of one or more family member does not lead to disease. Contrary to this, our analyses of prostates from 24-week-old Spry1- or Spry2-deficientmice, either hemizygous (+/-) or homozygous (-/-) for the null allele, revealed a significantly greater incidence of PIN compared to wild-type littermates. We further investigated redundancy of negative regulators in the clinical setting in a preliminary analysis of Gene Expression Omnibus and Oncomine human prostate cancer datasets. Consistent with our hypothesis, in two datasets analysed a significant cosuppression of SPRYs and SPREDs is evident. These findings demonstrate the importance of negative regulators of receptor tyrosine signalling, such as Spry, in the clinical setting, and highlight their importance for future pharmacopeia.
authors.affiliation: Disciplines of Physiology, School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Assinder
authors.affiliation: Disciplines of Physiology, School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Daniella
authors.initials: D
authors.lastname: Beniamen
authors.affiliation: Anatomy and Histology, School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Lovicu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; C504812:SPRED1 protein, human; C500760:SPRED2 protein, human; C486055:SPRY1 protein, human; C485561:SPRY2 protein, human; C433763:Spred1 protein, mouse; C433764:Spred2 protein, mouse; C425468:Spry1 protein, mouse; D005346:Fibroblast Growth Factors; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse