Akira Imamoto

Associate Professor
Research Summary
We are interested in elucidating mechanisms by which a mutation or combination of mutations affect broader network within and between cells during development. Our current model is DiGeorge/velocardiofacial/del22q11 syndrome (OMIM: 188400 and 192430), a contiguous gene syndrome in approximately 1 in 4000 live births. The common manifestations of this syndrome include cardiovascular defects, aplasia or hypoplasia of the thymus and parathyroid glands, and craniofacial anomalies. Urogenital defects, learning disabilities, and other psychiatric disorders are also common. Two 22q11 genes, TBX1 and CRKL, have been implicated in this syndrome. While they show a strong dosage-sensitive interaction in mouse models, they encode different classes of proteins. Tbx1 is a T-box transcription factor, while CRKL is an adapter protein presumably down stream of tyrosine kinases. To date, few direct links have been known between the signaling pathways in which they are involved. Using multitudes of techniques, we aim to find missing pieces to establish their functional links.
DiGeorge Syndrome, Velocardiofacial Syndrome, Cardiovascular Diseases, Pharyngeal Arches, Signal Transduction Pathways, Network, Gene
  • Osaka University, Osaka, Japan, DDS 03/1984
  • Osaka University, Osaka, Japan, PhD 03/1988
  • Fred Hutchinson Cancer Res Ctr, Seattle, WA, Post-doc 12/1996
Biosciences Graduate Program Association
  1. Kanazawa T, Michida H, Uchino Y, Ishihara A, Zhang S, Tabata S, Suzuki Y, Imamoto A, Okada M. Cell shape-based chemical screening reveals an epigenetic network mediated by focal adhesions. FEBS J. 2021 10; 288(19):5613-5628. View in: PubMed

  2. Imamoto A, Ki S, Li L, Iwamoto K, Maruthamuthu V, Devany J, Lu O, Kanazawa T, Zhang S, Yamada T, Hirayama A, Fukuda S, Suzuki Y, Okada M. Essential role of the Crk family-dosage in DiGeorge-like anomaly and metabolic homeostasis. Life Sci Alliance. 2020 02; 3(2). View in: PubMed

  3. Haller M, Mo Q, Imamoto A, Lamb DJ. Murine model indicates 22q11.2 signaling adaptor CRKL is a dosage-sensitive regulator of genitourinary development. Proc Natl Acad Sci U S A. 2017 05 09; 114(19):4981-4986. View in: PubMed

  4. Lopez-Rivera E, Liu YP, Verbitsky M, Anderson BR, Capone VP, Otto EA, Yan Z, Mitrotti A, Martino J, Steers NJ, Fasel DA, Vukojevic K, Deng R, Racedo SE, Liu Q, Werth M, Westland R, Vivante A, Makar GS, Bodria M, Sampson MG, Gillies CE, Vega-Warner V, Maiorana M, Petrey DS, Honig B, Lozanovski VJ, Salomon R, Heidet L, Carpentier W, Gaillard D, Carrea A, Gesualdo L, Cusi D, Izzi C, Scolari F, van Wijk JA, Arapovic A, Saraga-Babic M, Saraga M, Kunac N, Samii A, McDonald-McGinn DM, Crowley TB, Zackai EH, Drozdz D, Miklaszewska M, Tkaczyk M, Sikora P, Szczepanska M, Mizerska-Wasiak M, Krzemien G, Szmigielska A, Zaniew M, Darlow JM, Puri P, Barton D, Casolari E, Furth SL, Warady BA, Gucev Z, Hakonarson H, Flogelova H, Tasic V, Latos-Bielenska A, Materna-Kiryluk A, Allegri L, Wong CS, Drummond IA, D'Agati V, Imamoto A, Barasch JM, Hildebrandt F, Kiryluk K, Lifton RP, Morrow BE, Jeanpierre C, Papaioannou VE, Ghiggeri GM, Gharavi AG, Katsanis N, Sanna-Cherchi S. Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. N Engl J Med. 2017 02 23; 376(8):742-754. View in: PubMed

  5. Shigeno-Nakazawa Y, Kasai T, Ki S, Kostyanovskaya E, Pawlak J, Yamagishi J, Okimoto N, Taiji M, Okada M, Westbrook J, Satta Y, Kigawa T, Imamoto A. A pre-metazoan origin of the CRK gene family and co-opted signaling network. Sci Rep. 2016 Sep 30; 6:34349. View in: PubMed

  6. Zeng L, Ehrenreiter K, Menon J, Menard R, Kern F, Nakazawa Y, Bevilacqua E, Imamoto A, Baccarini M, Rosner MR. RKIP regulates MAP kinase signaling in cells with defective B-Raf activity. Cell Signal. 2013 May; 25(5):1156-65. View in: PubMed

  7. Seo JH, Wood LJ, Agarwal A, O'Hare T, Elsea CR, Griswold IJ, Deininger MW, Imamoto A, Druker BJ. A specific need for CRKL in p210BCR-ABL-induced transformation of mouse hematopoietic progenitors. Cancer Res. 2010 Sep 15; 70(18):7325-35. View in: PubMed

  8. Shemon AN, Eves EM, Clark MC, Heil G, Granovsky A, Zeng L, Imamoto A, Koide S, Rosner MR. Raf Kinase Inhibitory Protein protects cells against locostatin-mediated inhibition of migration. PLoS One. 2009 Jun 24; 4(6):e6028. View in: PubMed

  9. Seo JH, Suenaga A, Hatakeyama M, Taiji M, Imamoto A. Structural and functional basis of a role for CRKL in a fibroblast growth factor 8-induced feed-forward loop. Mol Cell Biol. 2009 Jun; 29(11):3076-87. View in: PubMed

  10. Zeng L, Imamoto A, Rosner MR. Raf kinase inhibitory protein (RKIP): a physiological regulator and future therapeutic target. Expert Opin Ther Targets. 2008 Oct; 12(10):1275-87. View in: PubMed

  11. Zhu F, Choi BY, Ma WY, Zhao Z, Zhang Y, Cho YY, Choi HS, Imamoto A, Bode AM, Dong Z. COOH-terminal Src kinase-mediated c-Jun phosphorylation promotes c-Jun degradation and inhibits cell transformation. Cancer Res. 2006 Jun 01; 66(11):5729-36. View in: PubMed

  12. Lee BC, Avraham S, Imamoto A, Avraham HK. Identification of the nonreceptor tyrosine kinase MATK/CHK as an essential regulator of immune cells using Matk/CHK-deficient mice. Blood. 2006 Aug 01; 108(3):904-7. View in: PubMed

  13. Guris DL, Duester G, Papaioannou VE, Imamoto A. Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome. Dev Cell. 2006 Jan; 10(1):81-92. View in: PubMed

  14. Moon AM, Guris DL, Seo JH, Li L, Hammond J, Talbot A, Imamoto A. Crkl deficiency disrupts Fgf8 signaling in a mouse model of 22q11 deletion syndromes. Dev Cell. 2006 Jan; 10(1):71-80. View in: PubMed

  15. Ballif BA, Arnaud L, Arthur WT, Guris D, Imamoto A, Cooper JA. Activation of a Dab1/CrkL/C3G/Rap1 pathway in Reelin-stimulated neurons. Curr Biol. 2004 Apr 06; 14(7):606-10. View in: PubMed

  16. Duan LJ, Imamoto A, Fong GH. Dual roles of the C-terminal Src kinase (Csk) during developmental vascularization. Blood. 2004 Feb 15; 103(4):1370-2. View in: PubMed

  17. Peterson AC, Marks RE, Fields PE, Imamoto A, Gajewski TF. T cell development and function in CrkL-deficient mice. Eur J Immunol. 2003 Oct; 33(10):2687-95. View in: PubMed

  18. Li L, Guris DL, Okura M, Imamoto A. Translocation of CrkL to focal adhesions mediates integrin-induced migration downstream of Src family kinases. Mol Cell Biol. 2003 Apr; 23(8):2883-92. View in: PubMed

  19. Lekmine F, Sassano A, Uddin S, Majchrzak B, Miura O, Druker BJ, Fish EN, Imamoto A, Platanias LC. The CrkL adapter protein is required for type I interferon-dependent gene transcription and activation of the small G-protein Rap1. Biochem Biophys Res Commun. 2002 Mar 08; 291(4):744-50. View in: PubMed

  20. Li L, Okura M, Imamoto A. Focal adhesions require catalytic activity of Src family kinases to mediate integrin-matrix adhesion. Mol Cell Biol. 2002 Feb; 22(4):1203-17. View in: PubMed

  21. Hagel M, George EL, Kim A, Tamimi R, Opitz SL, Turner CE, Imamoto A, Thomas SM. The adaptor protein paxillin is essential for normal development in the mouse and is a critical transducer of fibronectin signaling. Mol Cell Biol. 2002 Feb; 22(3):901-15. View in: PubMed

  22. Guris DL, Fantes J, Tara D, Druker BJ, Imamoto A. Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Nat Genet. 2001 Mar; 27(3):293-8. View in: PubMed

  23. Dey A, She H, Kim L, Boruch A, Guris DL, Carlberg K, Sebti SM, Woodley DT, Imamoto A, Li W. Colony-stimulating factor-1 receptor utilizes multiple signaling pathways to induce cyclin D2 expression. Mol Biol Cell. 2000 Nov; 11(11):3835-48. View in: PubMed

  24. Tsuda M, Matozaki T, Fukunaga K, Fujioka Y, Imamoto A, Noguchi T, Takada T, Yamao T, Takeda H, Ochi F, Yamamoto T, Kasuga M. Integrin-mediated tyrosine phosphorylation of SHPS-1 and its association with SHP-2. Roles of Fak and Src family kinases. J Biol Chem. 1998 May 22; 273(21):13223-9. View in: PubMed

  25. Zambrowicz BP, Imamoto A, Fiering S, Herzenberg LA, Kerr WG, Soriano P. Disruption of overlapping transcripts in the ROSA beta geo 26 gene trap strain leads to widespread expression of beta-galactosidase in mouse embryos and hematopoietic cells. Proc Natl Acad Sci U S A. 1997 Apr 15; 94(8):3789-94. View in: PubMed

  26. Xian W, Kiguchi K, Imamoto A, Rupp T, Zilberstein A, DiGiovanni J. Activation of the epidermal growth factor receptor by skin tumor promoters and in skin tumors from SENCAR mice. Cell Growth Differ. 1995 Nov; 6(11):1447-55. View in: PubMed

  27. Imamoto A, Wang XJ, Fujiki H, Walker SE, Beltrán LM, DiGiovanni J. Comparison of 12-O-tetradecanoylphorbol-13-acetate and teleocidin for induction of epidermal hyperplasia, activation of epidermal PKC isozymes and skin tumor promotion in SENCAR and C57BL/6 mice. Carcinogenesis. 1993 Apr; 14(4):719-24. View in: PubMed

  28. Imamoto A, Soriano P, Stein PL. Genetics of signal transduction: tales from the mouse. Curr Opin Genet Dev. 1994 Feb; 4(1):40-6. View in: PubMed

  29. Imamoto A, Soriano P. Disruption of the csk gene, encoding a negative regulator of Src family tyrosine kinases, leads to neural tube defects and embryonic lethality in mice. Cell. 1993 Jun 18; 73(6):1117-24. View in: PubMed

  30. Thomas SM, Soriano P, Imamoto A. Specific and redundant roles of Src and Fyn in organizing the cytoskeleton. Nature. 1995 Jul 20; 376(6537):267-71. View in: PubMed

  31. Imamoto A, Beltrán LM, DiGiovanni J. Differential mechanism for the inhibition of epidermal growth factor binding to its receptor on mouse keratinocytes by anthrones and phorbol esters. Carcinogenesis. 1990 Sep; 11(9):1543-9. View in: PubMed

  32. Imamoto A, Beltrán LM, DiGiovanni J. Evidence for autocrine/paracrine growth stimulation by transforming growth factor-alpha during the process of skin tumor promotion. Mol Carcinog. 1991; 4(1):52-60. View in: PubMed

  33. Imamoto A, Beltrán LM, Fujiki H, Chenicek KJ, DiGiovanni J. Enhanced induction of epidermal ornithine decarboxylase activity in C57BL/6 compared to DBA/2 mice by protein kinase C-activating skin tumor promoters: relevance to genetically mediated differences in promotion susceptibility. Carcinogenesis. 1992 Feb; 13(2):177-82. View in: PubMed

  34. DiGiovanni J, Imamoto A, Naito M, Walker SE, Beltrán L, Chenicek KJ, Skow L. Further genetic analyses of skin tumor promoter susceptibility using inbred and recombinant inbred mice. Carcinogenesis. 1992 Apr; 13(4):525-31. View in: PubMed