HtrA proteins as targets in therapy of cancer and other diseases.
BACKGROUND
The HtrA family proteins are serine proteases that are involved in important physiological processes, including maintenance of mitochondrial homeostasis, apoptosis and cell signaling. They are involved in the development and progression of several pathological processes such as cancer, neurodegenerative disorders and arthritic diseases.


METHODS
We present characteristics of the human HtrA1, HtrA2 and HtrA3 proteins, with the stress on their function in apoptosis and in the diseases. We describe regulation of the HtrAs' proteolytic activity, focusing on allosteric interactions of ligands/substrates with the PDZ domains, and make suggestions on how the HtrA proteolytic activity could be modified. Literature cited covers years 1996 - 2010.


RESULTS
An overview of the HtrAs' function/regulation and involvement in diseases (cancer, neurodegenerative disorders, arthritis), and ideas how modulation of their proteolytic activity could be used in therapies.


CONCLUSIONS
HtrA2 is the best target for cancer drug development. An increase in the HtrAs' proteolytic activity could be beneficial in cancer treatment, by stimulation of apoptosis, anoikis or necrosis of cancer cells, or by modulation of the TGF-beta signaling cascade; modulation of HtrA activity could be helpful in therapy of neurodegenerative diseases and arthritis.
Zurawa-Janicka
Dorota
D
University of Gdansk, Department of Biochemistry, Kladki 24, 80-822 Gdansk, Poland.
Skorko-Glonek
Joanna
J
Lipinska
Barbara
B
D000494:Allosteric Regulation; D000818:Animals; D023102:Anoikis / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001168:Arthritis / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D000074289:High-Temperature Requirement A Serine Peptidase 1; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008024:Ligands; D024101:Mitochondrial Proteins / Q000819:agonists / Q000737:chemistry / Q000502:physiology*; D009336:Necrosis / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D054731:PDZ Domains / Q000187:drug effects; D012697:Serine Endopeptidases / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta
D000970:Antineoplastic Agents; D008024:Ligands; D024101:Mitochondrial Proteins; D016212:Transforming Growth Factor beta; C474013:HTRA3 protein, human; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2