Identification of protein-protein interactions of human HtrA1.

The human heat shock protein HtrA1, a member of the HtrA family of serine proteases, is a evolutionarily highly conserved factor which displays a widespread pattern of expression. The yeast two-hybrid technique was employed to identify new cellular proteins physically interacting with HtrA1, and thus potential targets of this serine protease. An enzymatically inactive HtrA1 point mutant, HtrA1-S328A, was generated and used as bait in a yeast two-hybrid system. Fifty-two plasmids were isolated from primary positive yeast clones. Subsequent sequencing and BLAST analysis revealed cDNAs encoding for 13 different proteins. These putative binding partners of HtrA1 appeared to be a) components of extracellular matrix; b) factors related to signal pathways, and c) unknown proteins. Among the 13 positive clones identified and reported here, it is worth of note that the interaction of HtrA1 with tubulin and collagen (extracellular matrix proteins) and with tuberin (cytoplasmic protein) is confirmed by other studies, and this further supports previous findings in which HtrA1 can be found active as an intracytoplasmic protein or as secreted protein as well.

[1]  F. Segade Molecular evolution of the fibulins: implications on the functionality of the elastic fibulins. , 2010, Gene.

[2]  M. Caraglia,et al.  The Serine Protease HtrA1 Specifically Interacts and Degrades the Tuberous Sclerosis Complex 2 Protein , 2010, Molecular Cancer Research.

[3]  Y. Hathout,et al.  Identification of novel substrates for the serine protease HTRA1 in the human RPE secretome. , 2010, Investigative ophthalmology & visual science.

[4]  Vasilis Vasiliou,et al.  Evolutionary divergence and functions of the ADAM and ADAMTS gene families , 2009, Human Genomics.

[5]  Juan Liu,et al.  Meta-analysis of the association of the HTRA1 polymorphisms with the risk of age-related macular degeneration. , 2009, Experimental eye research.

[6]  C. Flannery,et al.  002 IDENTIFICATION OF A NOVEL HTRA1-SUSCEPTIBLE CLEAVAGE SITE IN HUMAN AGGRECAN: EVIDENCE FOR THE INVOLVEMENT OF HTRA1 IN AGGRECAN PROTEOLYSIS IN VIVO , 2009 .

[7]  J. Chien,et al.  HtrA serine proteases as potential therapeutic targets in cancer. , 2009, Current cancer drug targets.

[8]  J. Chien,et al.  Serine Protease HtrA1 Associates with Microtubules and Inhibits Cell Migration , 2009, Molecular and Cellular Biology.

[9]  S. Abramson,et al.  Inhibition of ADAMTS-7 and ADAMTS-12 degradation of cartilage oligomeric matrix protein by alpha-2-macroglobulin. , 2008, Osteoarthritis and cartilage.

[10]  P. Visca,et al.  The serine protease HtrA1 is a novel prognostic factor for human mesothelioma. , 2008, Pharmacogenomics.

[11]  J. Emerich,et al.  Changes in mRNA and protein levels of human HtrA1, HtrA2 and HtrA3 in ovarian cancer. , 2008, Clinical biochemistry.

[12]  R. Boot-Handford,et al.  HtrA1 Inhibits Mineral Deposition by Osteoblasts , 2008, Journal of Biological Chemistry.

[13]  E. Wylie,et al.  HtrA1: a novel regulator of physiological and pathological matrix mineralization? , 2007, Biochemical Society transactions.

[14]  W. Renner,et al.  Association of the HTRA1 -625G>A promoter gene polymorphism with exudative age-related macular degeneration in a Central European population. , 2007, Molecular vision.

[15]  Chi Pui Pang,et al.  HTRA1 promoter polymorphism in wet age-related macular degeneration. , 2007, Science.

[16]  N. Camp,et al.  A Variant of the HTRA1 Gene Increases Susceptibility to Age-Related Macular Degeneration , 2006, Science.

[17]  L. Salamonsen,et al.  Serine proteases HTRA1 and HTRA3 are down-regulated with increasing grades of human endometrial cancer. , 2006, Gynecologic oncology.

[18]  B. Vincenzi,et al.  Analysis of HtrA1 serine protease expression in human lung cancer. , 2006, Anticancer research.

[19]  Alfonso Baldi,et al.  Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity. , 2006, The Journal of clinical investigation.

[20]  W. Kong,et al.  ADAMTS‐7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  Tim Clausen,et al.  The Role of Human HtrA1 in Arthritic Disease* , 2006, Journal of Biological Chemistry.

[22]  John T. Wei,et al.  Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. , 2005, Cancer cell.

[23]  C. Gregory,et al.  Increased expression of δ-catenin/neural plakophilin-related armadillo protein is associated with the down-regulation and redistribution of E-cadherin and p120ctn in human prostate cancer , 2005 .

[24]  M. Kawaichi,et al.  Expression of mouse HtrA1 serine protease in normal bone and cartilage and its upregulation in joint cartilage damaged by experimental arthritis. , 2005, Bone.

[25]  Alfonso Baldi,et al.  Implications of the serine protease HtrA1 in amyloid precursor protein processing , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Masato Yano,et al.  Binding of proteins to the PDZ domain regulates proteolytic activity of HtrA1 serine protease. , 2004, The Biochemical journal.

[27]  A. Baldi,et al.  The Serine Protease HtrA1 Is Upregulated in the Human Placenta during Pregnancy , 2004, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[28]  Rameen Beroukhim,et al.  Molecular characterization of the tumor microenvironment in breast cancer. , 2004, Cancer cell.

[29]  M. Kawaichi,et al.  HtrA1 serine protease inhibits signaling mediated by Tgfβ family proteins , 2004, Development.

[30]  David I. Smith,et al.  A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer , 2004, Oncogene.

[31]  A. Baldi,et al.  Distribution of the Serine Protease HtrA1 in Normal Human Tissues , 2003, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[32]  L. Salamonsen,et al.  Identification and cloning of two isoforms of human high-temperature requirement factor A3 (HtrA3), characterization of its genomic structure and comparison of its tissue distribution with HtrA1 and HtrA2. , 2003, The Biochemical journal.

[33]  D. Noonan,et al.  The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells , 2002, Oncogene.

[34]  C. Southan,et al.  The HtrA family of proteases: implications for protein composition and cell fate. , 2002, Molecular cell.

[35]  J. Welsh,et al.  Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. , 2001, Cancer research.

[36]  C. Southan,et al.  Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. , 2000, European journal of biochemistry.

[37]  D. Kwiatkowski,et al.  Molecular genetic advances in tuberous sclerosis , 2000, Human Genetics.

[38]  K. Kosik,et al.  δ‐catenin is a nervous system‐specific adherens junction protein which undergoes dynamic relocalization during development , 2000, The Journal of comparative neurology.

[39]  C. Fusco,et al.  Characterization of a Novel Human Serine Protease That Has Extensive Homology to Bacterial Heat Shock Endoprotease HtrA and Is Regulated by Kidney Ischemia* , 2000, The Journal of Biological Chemistry.

[40]  C. Leonetti,et al.  Increase of cisplatin sensitivity by c-myc antisense oligodeoxynucleotides in a human metastatic melanoma inherently resistant to cisplatin. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[41]  D. Luk,et al.  Human HtrA, an Evolutionarily Conserved Serine Protease Identified as a Differentially Expressed Gene Product in Osteoarthritic Cartilage* , 1998, The Journal of Biological Chemistry.

[42]  W. Franke,et al.  Identification and localization of a neurally expressed member of the plakoglobin/armadillo multigene family. , 1997, Differentiation; research in biological diversity.

[43]  M. Lovett,et al.  Presenilin 1 interaction in the brain with a novel member of the Armadillo family , 1997, Neuroreport.

[44]  J. Zumbrunn,et al.  Primary structure of a putative serine protease specific for IGF‐binding proteins , 1996, FEBS letters.

[45]  A. Green,et al.  The tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor. , 1994, Human molecular genetics.

[46]  A. Green,et al.  Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients , 1994, Nature Genetics.

[47]  P. Byers,et al.  Defective folding and stable association with protein disulfide isomerase/prolyl hydroxylase of type I procollagen with a deletion in the pro alpha 2(I) chain that preserves the Gly-X-Y repeat pattern. , 1992, The Journal of biological chemistry.

[48]  E. Ruoslahti,et al.  Fibulin, a novel protein that interacts with the fibronectin receptor β subunit cytoplasmic domain , 1989, Cell.

[49]  C. Georgopoulos,et al.  Sequence analysis and regulation of the htrA gene of Escherichia coli: a sigma 32-independent mechanism of heat-inducible transcription. , 1988, Nucleic acids research.

[50]  J. Beckwith,et al.  An Escherichia coli mutation preventing degradation of abnormal periplasmic proteins. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[51]  A. Baldi,et al.  Expression patterns of two serine protease HtrA1 forms in human placentas complicated by preeclampsia with and without intrauterine growth restriction. , 2009, Placenta.