1. Learning to Extract Proteins and their Interactions from Medline Abstracts Razvan Bunescu, Ruifang Ge, Rohit J. Kate, Yuk Wah Wong Edward M. Marcotte, Arun Ramani Department of Computer Sciences Institute for Cellular and Molecular Biology University of Texas at Austin Raymond J. Mooney Department of Computer Sciences

4. 1 taaccctaac cctaacccta accctaaccc taaccctaac cctaacccta accctaaccc 61 taaccctaac cctaacccta accctaaccc taaccctaac cctaacccaa ccctaaccct 121 aaccctaacc ctaaccctaa ccctaacccc taaccctaac cctaacccta accctaacct 181 aaccctaacc ctaaccctaa ccctaaccct aaccctaacc ctaaccctaa cccctaaccc 241 taaccctaaa ccctaaaccc taaccctaac cctaacccta accctaaccc caaccccaac 301 cccaacccca accccaaccc caaccctaac ccctaaccct aaccctaacc ctaccctaac 361 cctaacccta accctaaccc taaccctaac ccctaacccc taaccctaac cctaacccta 421 accctaaccc taaccctaac ccctaaccct aaccctaacc ctaaccctcg cggtaccctc 481 agccggcccg cccgcccggg tctgacctga ggagaactgt gctccgcctt cagagtacca 541 ccgaaatctg tgcagaggac aacgcagctc cgccctcgcg gtgctctccg ggtctgtgct 601 gaggagaacg caactccgcc ggcgcaggcg cagagaggcg cgccgcgccg gcgcaggcgc 661 agacacatgc tagcgcgtcg gggtggaggc gtggcgcagg cgcagagagg cgcgccgcgc 721 cggcgcaggc gcagagacac atgctaccgc gtccaggggt ggaggcgtgg cgcaggcgca 781 gagaggcgca ccgcgccggc gcaggcgcag agacacatgc tagcgcgtcc aggggtggag 841 gcgtggcgca ggcgcagaga cgcaagccta cgggcggggg ttgggggggc gtgtgttgca 901 ggagcaaagt cgcacggcgc cgggctgggg cggggggagg gtggcgccgt gcacgcgcag 961 aaactcacgt cacggtggcg cggcgcagag acgggtagaa cctcagtaat ccgaaaagcc 1021 gggatcgacc gccccttgct tgcagccggg cactacagga cccgcttgct cacggtgctg 1081 tgccagggcg ccccctgctg gcgactaggg caactgcagg gctctcttgc ttagagtggt ... 5641 gctccagggc ccgctcacct tgctcctgct ccttctgctg ctgcttctcc agctttcgct 5701 ccttcatgct gcgcagcttg gccttgccga tgcccccagc ttggcggatg gactctagca 5761 gagtggccag ccaccggagg ggtcaaccac ttccctggga gctccctgga ctggagccgg 5821 gaggtgggga acagggcaag gaggaaaggc tgctcaggca gggctgggga agcttactgt 5881 gtccaagagc ctgctgggag ggaagtcacc tcccctcaaa cgaggagccc tgcgctgggg 5941 aggccggacc tttggagact gtgtgtgggg gcctgggcac tgacttctgc aaccacctga 6001 gcgcgggcat cctgtgtgca gatactccct gcttcctctc tagcccccac cctgcagagc 6061 tggacccctg agctagccat gctctgacag tctcagttgc acacacgagc cagcagaggg 6121 gttttgtgcc acttctggat gctagggtta cactgggaga cacagcagtg aagctgaaat 6181 gaaaaatgtg ttgctgtagt ttgttattag accccttctt tccattggtt taattaggaa 6241 tggggaaccc agagcctcac ttgttcaggc tccctctgcc ctagaagtga gaagtccaga 6301 gctctacagt ttgaaaacca ctattttatg aaccaagtag aacaagatat ttgaaatgga 6361 aactattcaa aaaattgaga atttctgacc acttaacaaa cccacagaaa atccacccga 6421 gtgcactgag cacgccagaa atcaggtggc ctcaaagagc tgctcccacc tgaaggagac 6481 gcgctgctgc tgctgtcgtc ctgcctggcg ccttggccta caggggccgc ggttgagggt 6541 gggagtgggg gtgcactggc cagcacctca ggagctgggg gtggtggtgg gggcggtggg 6601 ggtggtgtta gtaccccatc ttgtaggtct gaaacacaaa gtgtggggtg tctagggaag ... and 3x10 9 more... Starting at the tip of chromosome 1...

6. Sample Gene Network

7. Yeast Gene Network ~5,800 genes ~5,800 proteins x 2-10 interactions/protein ~12,000 - 60,000 interactions Yeast ~ 10-20,000 known ==> ~1/3 of the way to a complete map!

8. Human Gene Network ~40,000 genes >>40,000 proteins x 2-10 interactions/protein >>80,000 - 400,000 interactions <5,000 known ==> approx. 1% of the complete map! ==> We’re a long ways from the complete map

9. Relevant Sources of Data Biological literature ~14 million documents DNA sequence data ~10 10 nucleotides Gene expression data ~10 8 measurements, but... DNA polymorphisms ~10 7 known Gene inactivation (knockout) studies ~10 5 Protein structure data ~10 4 structures Protein interaction data ~10 4 interactions, but… Protein expression data ~10 4 measurements, but... Protein location data ~10 4 measurements

12. TI - Two potentially oncogenic cyclins, cyclin A and cyclin D1, share common properties of subunit configuration, tyrosine phosphorylation and physical association with the Rb protein AB - Originally identified as a ‘mitotic cyclin’, cyclin A exhibits properties of growth factor sensitivity, susceptibility to viral subversion and association with a tumor-suppressor protein, properties which are indicative of an S-phase-promoting factor (SPF) as well as a candidate proto-oncogene. Other recent studies have identified human cyclin D1 (PRAD1) as a putative G1 cyclin and candidate proto-oncogene. However, the specific enzymatic activities and, hence, the precise biochemical mechanisms through which cyclins function to govern cell cycle progression remain unresolved. In the present study we have investigated the coordinate interactions between these two potentially oncogenic cyclins, cyclin-dependent protein kinase subunits (cdks) and the Rb tumor-suppressor protein. The distribution of cyclin D isoforms was modulated by serum factors in primary fetal rat lung epithelial cells. Moreover, cyclin D1 was found to be phosphorylated on tyrosine residues in vivo and, like cyclin A, was readily phosphorylated by pp60c-src in vitro. In synchronized human osteosarcoma cells, cyclin D1 is induced in early G1 and becomes associated with p9Ckshs1, a Cdk-binding subunit. Immunoprecipitation experiments with human osteosarcoma cells and Ewing’s sarcoma cells demonstrated that cyclin D1 is associated with both p34cdc2 and p33cdk2, and that cyclin D1 immune complexes exhibit appreciable histone H1 kinase activity. Immobilized, recombinant cyclins A and D1 were found to associate with cellular proteins in complexes that contain the p105Rb protein. This study identifies several common aspects of cyclin biochemistry, including tyrosine phosphorylation and the potential to interact directly or indirectly with the Rb protein, that may ultimately relate membrane-mediated signaling events to the regulation of gene expression. Sample Medline Abstract

13. TI - Two potentially oncogenic cyclins, cyclin A and cyclin D1 , share common properties of subunit configuration, tyrosine phosphorylation and physical association with the Rb protein AB - Originally identified as a ‘mitotic cyclin’, cyclin A exhibits properties of growth factor sensitivity, susceptibility to viral subversion and association with a tumor-suppressor protein, properties which are indicative of an S-phase-promoting factor ( SPF ) as well as a candidate proto-oncogene. Other recent studies have identified human cyclin D1 ( PRAD1 ) as a putative G1 cyclin and candidate proto-oncogene. However, the specific enzymatic activities and, hence, the precise biochemical mechanisms through which cyclins function to govern cell cycle progression remain unresolved. In the present study we have investigated the coordinate interactions between these two potentially oncogenic cyclins, cyclin-dependent protein kinase subunits (cdks) and the Rb tumor-suppressor protein. The distribution of cyclin D isoforms was modulated by serum factors in primary fetal rat lung epithelial cells. Moreover, cyclin D1 was found to be phosphorylated on tyrosine residues in vivo and, like cyclin A , was readily phosphorylated by pp60c-src in vitro. In synchronized human osteosarcoma cells, cyclin D1 is induced in early G1 and becomes associated with p9Ckshs1 , a Cdk-binding subunit. Immunoprecipitation experiments with human osteosarcoma cells and Ewing’s sarcoma cells demonstrated that cyclin D1 is associated with both p34cdc2 and p33cdk2 , and that cyclin D1 immune complexes exhibit appreciable histone H1 kinase activity. Immobilized, recombinant cyclins A and D1 were found to associate with cellular proteins in complexes that contain the p105Rb protein. This study identifies several common aspects of cyclin biochemistry, including tyrosine phosphorylation and the potential to interact directly or indirectly with the Rb protein, that may ultimately relate membrane-mediated signaling events to the regulation of gene expression. Sample Medline Abstract

14. Sample Medline Abstract TI - Two potentially oncogenic cyclins, cyclin A and cyclin D1 , share common properties of subunit configuration, tyrosine phosphorylation and physical association with the Rb protein AB - Originally identified as a ‘mitotic cyclin’, cyclin A exhibits properties of growth factor sensitivity, susceptibility to viral subversion and association with a tumor-suppressor protein, properties which are indicative of an S-phase-promoting factor ( SPF ) as well as a candidate proto-oncogene. Other recent studies have identified human cyclin D1 ( PRAD1 ) as a putative G1 cyclin and candidate proto-oncogene. However, the specific enzymatic activities and, hence, the precise biochemical mechanisms through which cyclins function to govern cell cycle progression remain unresolved. In the present study we have investigated the coordinate interactions between these two potentially oncogenic cyclins, cyclin-dependent protein kinase subunits (cdks) and the Rb tumor-suppressor protein. The distribution of cyclin D isoforms was modulated by serum factors in primary fetal rat lung epithelial cells. Moreover, cyclin D1 was found to be phosphorylated on tyrosine residues in vivo and, like cyclin A , was readily phosphorylated by pp60c-src in vitro. In synchronized human osteosarcoma cells, cyclin D1 is induced in early G1 and becomes associated with p9Ckshs1 , a Cdk-binding subunit. Immunoprecipitation experiments with human osteosarcoma cells and Ewing’s sarcoma cells demonstrated that cyclin D1 is associated with both p34cdc2 and p33cdk2 , and that cyclin D1 immune complexes exhibit appreciable histone H1 kinase activity. Immobilized, recombinant cyclins A and D1 were found to associate with cellular proteins in complexes that contain the p105Rb protein. This study identifies several common aspects of cyclin biochemistry, including tyrosine phosphorylation and the potential to interact directly or indirectly with the Rb protein, that may ultimately relate membrane-mediated signaling events to the regulation of gene expression.

26. Protein Name Extraction Results (Bunescu et al., 2004)

30. Protein Name Extraction Results (Yapex)

31. Collective Classification of Web Pages [ Taskar, Abbeel & Koller 2002 ]

32. Collective Information Extraction The control of human ribosomal protein L22 ( rpL22 ) to enter into the nucleolus and its ability to be assembled into the ribosome is regulated by its sequence . The nuclear import of rpL22 depends on a classical nuclear localization signal of four lysines at positions 13 – 16 … Once it reaches the nucleolus , the question of whether rpL22 is assembled into the ribosome depends upon the presence of the N - domain . e 1 e 2 e 3 e 4 ribosomal protein L22 ( rpL22 ) of rpL22 depends whether rpL22 is acronym repetition repetition repetition overlap e 5 L22

35. Experimental Results – Yapex

36. Experimental Results – AIMed

39. Generalizing Rules using Longest Common Subsequence The self - association site appears to be formed by interactions between helices 1 and 2 of beta spectrin repeat 17 of one dimer with helix 3 of alpha spectrin repeat 1 of the other dimer to form two combined alpha - beta triple - helical segments . Title - Physical and functional interactions between the transcriptional inhibitors Id3 and ITF-2b . - (7) interactions (0) between (5) PROT (9) PROT (17) .

40. Protein Interaction Extraction Results (gold-standard protein tags)

41. Protein Interaction Extraction Results (automated protein tags)

48. Integrating Extracted Data with Existing Databases Extracted : 6,580 interactions between 3,737 human proteins Total: 31,609 interactions between 7,748 human proteins.

49. Filtered Co-citation Analysis: Evaluation

52. Evaluation: ERK vs ELCS vs Manual