This study was funded by the National Health and Medical Research Council, the Victorian Cancer Agency and a scholarship from the Chinese Scholarship Council. The authors have no conflicts of interest to declare.

BACKGROUND Members of the cysteine-rich secretory proteins (CRISPS), antigen 5 (Ag5) and pathogenesis-related 1 (Pr-1) (CAP) superfamily of proteins are found across the bacterial, fungal, plant and animal kingdoms. Although many CAP superfamily proteins remain poorly characterized, over the past decade evidence has accumulated, which provides insights into the functional roles of these proteins in various processes, including fertilization, immune defence and subversion, pathogen virulence, venom toxicology and cancer biology. OBJECTIVE AND RATIONALE The aim of this article is to summarize the current state of knowledge on CAP superfamily proteins in mammalian fertility, organismal homeostasis and disease pathogenesis. SEARCH METHODS The scientific literature search was undertaken via PubMed database on all articles published prior to November 2019. Search terms were based on following keywords: ‘CAP superfamily’, ‘CRISP’, ‘Cysteine-rich secretory proteins’, ‘Antigen 5’, ‘Pathogenesis-related 1’, ‘male fertility’, ‘CAP and CTL domain containing’, ‘CRISPLD1’, ‘CRISPLD2’, ‘bacterial SCP’, ‘ion channel regulator’, ‘CatSper’, ‘PI15’, ‘PI16’, ‘CLEC’, ‘PRY proteins’, ‘ASP proteins’, ‘spermatogenesis’, ‘epididymal maturation’, ‘capacitation’ and ‘snake CRISP’. In addition to that, reference lists of primary and review article were reviewed for additional relevant publications. OUTCOMES In this review, we discuss the breadth of knowledge on CAP superfamily proteins with regards to their protein structure, biological functions and emerging significance in reproduction, health and disease. We discuss the evolution of CAP superfamily proteins from their otherwise unembellished prokaryotic predecessors into the multi-domain and neofunctionalized members found in eukaryotic organisms today. At least in part because of the rapid evolution of these proteins, many inconsistencies in nomenclature exist within the literature. As such, and in part through the use of a maximum likelihood phylogenetic analysis of the vertebrate CRISP subfamily, we have attempted to clarify this confusion, thus allowing for a comparison of orthologous protein function between species. This framework also allows the prediction of functional relevance between species based on sequence and structural conservation. WIDER IMPLICATIONS This review generates a picture of critical roles for CAP proteins in ion channel regulation, sterol and lipid binding and protease inhibition, and as ligands involved in the induction of multiple cellular processes.

Identifying the factors stimulating prostate cancer cells migration and invasion has the potential to bring new therapeutic targets to the clinic. Cysteine-rich secretory protein 3 (CRISP3) is one of the most highly upregulated proteins during the transition of a healthy human prostatic epithelium to prostate cancer. Here we show using a genetically engineered mouse model of prostate cancer that CRISP3 production greatly facilitates disease progression from carcinoma in situ to invasive prostate cancer in vivo. This interpretation was confirmed using both human and mouse prostate cancer cell lines, which showed that exposure to CRISP3 enhanced cell motility and invasion. Further, using mass spectrometry, we show that CRISP3 induces changes in abundance of a subset of cell-cell adhesion proteins, including LASP1 and TJP1 both in vivo and in vitro. Collectively, these data identify CRISP3 as being pro-tumorigenic in the prostate and validate it as a potential target for therapeutic intervention.

Cysteine-rich secretory protein 3 (CRISP3) is one of the most highly up-regulated proteins during the transition from a healthy human prostatic epithelium to prostate cancer. The role of CRISP3 within this process has not however, been defined. Here we show using a genetically engineered mouse model of prostate cancer, that CRISP3 production greatly facilitates disease progression from carcinoma in situ to invasive prostate cancer in vivo. This observation was further validated using both human and mouse prostate cancer cell lines, which showed that exposure to CRISP3 enhanced cell motility and invasion. Further,using mass spectrometry, we showed that this activity is induced, at least in part, via changes in cell-cell adhesion proteins, including LASP1 and TJP1 both in vivo and in vitro. Collectively, these data identify CRISP3 as being pro-tumorigenic in the prostate and validate it as a bona fide marker of aggressive prostate cancer and a potential target for therapeutic intervention. Citation Format: Luc Furic, Marianna Volpert, Jinghua Hu, Anne O'Connor, Richard J. Rebello, Shivakumar Keerthikumar, Jemma Evans, Jo Merriner, John Pedersen, Gail P. Risbridger, Peter McIntyre, Moira K. O'Bryan. Cysteine-rich secretory protein 3 expression leads to invasive prostate cancer by modulating cell motility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 155.