Abstract
The 15 members of the kallikrein-related serine peptidase (KLK) family have diverse tissue-specific expression profiles and roles in a range of cellular processes, including proliferation, migration, invasion, differentiation, inflammation and angiogenesis that are required in both normal physiology as well as pathological conditions. These roles require cleavage of a range of substrates, including extracellular matrix proteins, growth factors, cytokines as well as other proteinases. In addition, it has been clear since the earliest days of KLK research that cleavage of cell surface substrates is also essential in a range of KLK-mediated cellular processes where these peptidases are essentially acting as agonists and antagonists. In this review we focus on these KLK-regulated cell surface receptor systems including bradykinin receptors, proteinase-activated receptors, as well as the plasminogen activator, ephrins and their receptors, and hepatocyte growth factor/Met receptor systems and other plasma membrane proteins. From this analysis it is clear that in many physiological and pathological settings KLKs have the potential to regulate multiple receptor systems simultaneously; an important issue when these peptidases and substrates are targeted in disease.
About the authors
Ying Dong studied Medicine at Beijing Union Medical College, China, where she then worked as an obstetrician and gynaecologist. Her PhD study was on biomarkers for ovarian cancer progression and treatment responses at the University of Queensland. She is a Research Fellow in the Cancer Program, Translational Research Institute, Queensland University of Technology. Her research is focused on understanding the functions of kallikrein proteases and the role of the tumour microenvironment in ovarian cancer.
Brittney Harrington completed her studies of Bachelor of Science with Honours at the University of Queensland. Brittney is currently performing research for her PhD at the Mater Medical Research Institute studying the role of the cell membrane protein CDCP1 in ovarian cancer progression, in particular in association with the tumour microenvironment.
Mark Adams undertook his undergraduate and honours degree studies at the Queensland University of Technology. He completed his PhD in 2012 at the Mater Medical Research Institute whilst supervised by Associate Professor John Hooper studying the protease-activated receptor-2 in cancer. He currently works as a postdoctoral research fellow based at the Translational Research Institute, Queensland University of Technology, examining the role of genomic instability in cancer progression.
Andreas Wortmann studied Biotechnology at the University of Applied Sciences Furtwangen in Germany. After three years in the pharmaceutical industry working on the pre-clinical development of anti-tumour compounds, he studied for his PhD in cancer cell biology at the Institute of Health and Biomedical Innovation, Queensland University of Technology. In early 2011, he received his PhD and continued with two years of post-doctoral research in cancer cell biology and medical bionics. Since early 2013, he has worked at the Australian Therapeutic Goods Administration, in the evaluation of risk-management plans for high risk prescription medicines.
Sally-Anne Stephenson completed a PhD at the University of Queensland, Australia in 1998. Following post-doctoral studies at Queensland University of Technology (QUT), Brisbane where she identified KLK4 in the human kallikrein locus and at The Queen Elizabeth Hospital, Adelaide where she identified EphB4 as a protein increased in colon cancer, she started the Eph receptor biology group now at QUT’s Institute of Health and Biomedical Innovation and part of the Translational Research Institute.
Jessica Lisle gained both her Bachelor’s degree and Honours in Applied Science from the Queensland University of Technology. She is currently a PhD student studying protease regulation of the EphB4 receptor by kallikrein-related peptidase 4 in prostate cancer at the Translational Research Institute, Queensland University of Technology.
Professor Adrian Herington studied Biochemistry at Monash University in Melbourne, Australia, where he received his PhD for studies in the growth hormone (GH) and insulin-like growth factor (IGF) fields in 1973. After postdoctoral work in the USA, he continued this work leading independent research groups at the Prince Henry’s Hospital Research Centre and the Royal Children’s Hospital in Melbourne, until moving to the Queensland University of Technology in Brisbane in 1995. Currently, he heads QUT’s Institute of Health & Biomedical Innovation’s research teams at the Translational Research Institute in Brisbane. His personal research focusses on both the ghrelin axis and the receptor tyrosine kinase EphB4 in hormone-dependent cancers of the prostate and breast.
John Hooper studied chemistry at the University of Queensland and performed his PhD research on serine proteases in cancer and other pathologies at the Queensland Institute of Medical Research. His postdoctoral work at The Scripps Research Institute involved the use of animal models to examine proteases and receptor systems in metastasis and angiogenesis. His laboratory at the Mater Medical Research Institute – University of Queensland investigates molecular aberrations that could be used as biomarkers and/or therapeutic targets for late stage cancer.
Distinguished Professor Judith Clements studied Endocrinology at Monash University in Melbourne, Australia where she received her PhD in 1989. Since then she has been a Research Fellow, Senior Research Fellow and Principal Research Fellow of the Australian National Health and Medical Research Council. She is Head of the Cancer Program at the Institute of Health and Biomedical Innovation and Translational Research Institute at Queensland University of Technology and Scientific Director of the Australian Prostate Cancer Research Centre-Queensland. Her research interests are focused on mechanistic and translational studies of the role of the kallikrein-related serine peptidases in hormone dependent cancers, particularly prostate and ovarian cancers.
Acknowledgments
This work was supported by funds from the National Health and Medical Research Council (NHMRC) of Australia (grants 550523, 614206 JAC, YD, JDH), the Australia India Strategic Research Fund (grant BF060023, JAC, YD), The Cancer Council Queensland, Australian Prostate Cancer Foundation of Australia (JDH, JAC, YD, SAS), and Wesley Research Institute (JDH, JAC, YD). Queensland University of Technology (SAS, AH, JL), JDH is an Australian Research Council Future Fellow and JAC is a NHMRC Principal Research Fellow.
Disclosure of potential conflicts of interest: No potential conflicts of interest are disclosed.
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