Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer
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Henry R. Maun
Abstract
Proteases represent a large class of enzymes with crucial biological functions. Although targeting various relevant proteases for therapeutic intervention has been widely investigated, structurally related proteins lacking proteolytic activity (pseudo-proteases) have received relatively little attention. Two distinct clinically relevant cancer pathways that contain signaling proteins with pseudo-protease domains include the Met and Hedgehog (Hh) pathways. The receptor tyrosine kinase Met pathway is driven by hepatocyte growth factor (HGF), a plasminogen-related ligand that binds Met and activates intracellular pathways resulting in cell proliferation, angiogenesis, motility and survival. HGF is a disulfide-linked α/β-heterodimer having a trypsin serine protease-like β-chain. The Hh pathway is driven by Sonic hedgehog (Shh), which has a Zn2+ metalloprotease fold and binds Patched1 (Ptc1), which de-represses Smoothened and ultimately activates Gli-dependent transcription. Although HGF and Shh differ in structure and function, the pseudo-catalytic sites of both HGF and Shh are crucial for signal transduction. For HGF, this region binds the Met β-propeller domain, which leads to Met dimerization and signaling. For Hh, this region binds to the antagonist receptor Hedgehog-interacting protein (Hhip) and most probably to Ptc1 as well. Thus, for both HGF and Hh pathways, targeting ligand pseudo-active sites represents a new strategy for regulation.
©2010 by Walter de Gruyter Berlin New York
Articles in the same Issue
- Guest Editorial
- Highlight: The Biology of Proteolytic Systems
- Highlight: 6th General Meeting of the International Proteolysis Society
- Structure, mechanism and inhibition of γ-secretase and presenilin-like proteases
- Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions
- Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce β-amyloid related to Alzheimer's disease
- Proteases in lymphocyte killer function: redundancy, polymorphism and questions remaining
- Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer
- Proteolysis of platelet receptors in humans and other species
- Blunting the knife: development of vaccines targeting digestive proteases of blood-feeding helminth parasites
- Impaired turnover of autophagolysosomes in cathepsin L deficiency
- Nuclear cysteine cathepsin variants in thyroid carcinoma cells
- Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer
- Cathepsin E enhances anticancer activity of doxorubicin on human prostate cancer cells showing resistance to TRAIL-mediated apoptosis
- Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DP8)
- Molecular contortionism – on the physical limits of serpin ‘loop-sheet’ polymers
- The substrate specificity profile of human granzyme A
- Use of granzyme B-based fluorescent protein reporters to monitor granzyme distribution and granule integrity in live cells
Articles in the same Issue
- Guest Editorial
- Highlight: The Biology of Proteolytic Systems
- Highlight: 6th General Meeting of the International Proteolysis Society
- Structure, mechanism and inhibition of γ-secretase and presenilin-like proteases
- Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions
- Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce β-amyloid related to Alzheimer's disease
- Proteases in lymphocyte killer function: redundancy, polymorphism and questions remaining
- Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer
- Proteolysis of platelet receptors in humans and other species
- Blunting the knife: development of vaccines targeting digestive proteases of blood-feeding helminth parasites
- Impaired turnover of autophagolysosomes in cathepsin L deficiency
- Nuclear cysteine cathepsin variants in thyroid carcinoma cells
- Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer
- Cathepsin E enhances anticancer activity of doxorubicin on human prostate cancer cells showing resistance to TRAIL-mediated apoptosis
- Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DP8)
- Molecular contortionism – on the physical limits of serpin ‘loop-sheet’ polymers
- The substrate specificity profile of human granzyme A
- Use of granzyme B-based fluorescent protein reporters to monitor granzyme distribution and granule integrity in live cells
