Activation of membrane-bound proteins and receptor systems: a link between tissue kallikrein and the KLK-related peptidases

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.

Eph Receptors and Ephrins: Therapeutic Opportunities

“…Proteases of the ADAM (A disintegrin and metalloproteinase) family, such as ADAM10 and ADAM12, can associate with EphA receptors and cleave in trans ephrin-As expressed in neighboring cells, allowing EphA/ephrin-A endocytosis and cell separation or weakening intercellular junctions (8; 170). Ephrin-Bs can also be cleaved extracellularly by ADAM8, ADAM10 and ADAM13 to regulate angiogenesis, neural tube morphogenesis, and induction of cranial neural crest (8; 171; 172). Interaction with EphB receptors can enhance ephrin-B extracellular cleavage by MMPs, such as MMP8 in the case of ephrin-B1 (171), followed by intramembrane cleavage by γ-secretase (8).…”

“…Ephrin-Bs can also be cleaved extracellularly by ADAM8, ADAM10 and ADAM13 to regulate angiogenesis, neural tube morphogenesis, and induction of cranial neural crest (8; 171; 172). Interaction with EphB receptors can enhance ephrin-B extracellular cleavage by MMPs, such as MMP8 in the case of ephrin-B1 (171), followed by intramembrane cleavage by γ-secretase (8). The ephrin-B cytoplasmic fragment generated can enhance phosphorylation of uncleaved ephrin-Bs by SRC (8) and translocate to the nucleus to regulate transcription (8; 171).…”

“…Interaction with EphB receptors can enhance ephrin-B extracellular cleavage by MMPs, such as MMP8 in the case of ephrin-B1 (171), followed by intramembrane cleavage by γ-secretase (8). The ephrin-B cytoplasmic fragment generated can enhance phosphorylation of uncleaved ephrin-Bs by SRC (8) and translocate to the nucleus to regulate transcription (8; 171). RHBDL2, a rhomboid transmembrane serine protease, cleaves the transmembrane segment of ephrin-Bs, with a preference for ephrin-B3 (171).…”

“…The ephrin-B cytoplasmic fragment generated can enhance phosphorylation of uncleaved ephrin-Bs by SRC (8) and translocate to the nucleus to regulate transcription (8; 171). RHBDL2, a rhomboid transmembrane serine protease, cleaves the transmembrane segment of ephrin-Bs, with a preference for ephrin-B3 (171). EphA receptors such as EphA4 can be cleaved in the second fibronectin domain by MMPs activated by calcium influx independently of ephrin binding, followed by intramembrane cleavage by γ-secretase (8).…”

Murine, but not human, ephrin-B2 can be efficiently cleaved by the serine protease kallikrein-4: Implications for xenograft models of human prostate cancer

“…The serine protease kallikrein-related peptidase 4 (KLK4) is over-expressed and secreted from PCa cells and plays an increasingly recognised key role in PCa cell biology, cleaving a number of known tumour modulators and extracellular matrix proteins [28][29][30][31][32][33]. Increased expression of KLK4 in 60 PCa patient samples when compared with 59 benign prostatic hyperplasia (BPH) samples positively correlated with PCa stage and pre-operative PSA serum concentration [28].…”