Skip to main content

Advertisement

SpringerLink
Log in

Tom1l2 hypomorphic mice exhibit increased incidence of infections and tumors and abnormal immunologic response

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

Studies have shown that the TOM1 family of proteins, including TOM1 and TOM1L1, are actively involved in endosomal trafficking and function in the immune response. However, much less is known about the function of TOM1L2. To understand the biological importance of TOM1L2 and the potential significance of its cellular role, we created and evaluated Tom1l2 gene-trapped mice with reduced Tom1l2 expression. Mice hypomorphic for Tom1l2 exhibited numerous infections and tumors compared to wild-type littermates. Associated with this increased risk for infection and tumor formation, apparently healthy Tom1l2 hypomorphs also had splenomegaly, elevated B- and T-cell counts, and an impaired humoral response, although at a reduced penetrance. Furthermore, cellular localization studies showed that a Tom1l2-GFP fusion protein colocalizes with Golgi compartments, supporting the role of Tom1l2 in cellular trafficking, while molecular modeling and bioinformatic analysis of Tom1l2 illustrated a structural basis for a functional role in trafficking. These results indicate a role for Tom1l2 in the immune response and possibly in tumor suppression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

Tom1l2:

Target of Myb-1-like 2

Tom1l1:

Target of Myb-1-like 1

Tom1:

Target of Myb-1

Tollip:

Toll interacting protein

SMS:

Smith-Magenis syndrome

VHS:

Vps27p/Hrs/Stam

GAT:

GGA and Tom

GGA:

Golgi localizing, Gamma-adaptin ear homology domain, ADP-ribosylation factor-binding protein

ARF1:

ADP-ribosylation factor 1

SFK:

Src family of protein kinases

IL-1R1:

Interleukin-1 receptor type 1

SHIRPA:

SmithKline Beecham Pharmaceuticals, Harwell MRC Mouse Genome Centre and Mammalian Genetics Unit, Imperial College School of Medicine at St Mary’s, Royal London Hospital, St Bartholomew’s, and the Royal London School of Medicine, Phenotype, Assessment

References

  • Akutsu M, Kawasaki M, Katoh Y, Shiba T, Yamaguchi Y et al (2005) Structural basis for recognition of ubiquitinated cargo by Tom1-GAT domain. FEBS Lett 579:5385–5391

    Article  PubMed  CAS  Google Scholar 

  • Aligayer H, Boyd DD, Heiss MM, Abdalla EK, Curley SA et al (2002) Activation of Src kinase in primary colorectal carcinoma: an indicator of poor clinical prognosis. Cancer 94:344–351

    Article  PubMed  CAS  Google Scholar 

  • Amsterdam A, Burgess S, Golling G, Chen W, Sun Z et al (1999) A large-scale insertional mutagenesis screen in zebrafish. Genes Dev 13:2713–2724

    Article  PubMed  CAS  Google Scholar 

  • Atiye J, Wolf M, Kaur S, Monni O, Bohling T et al (2005) Gene amplifications in osteosarcoma-CGH microarray analysis. Genes Chromosomes Cancer 42:158–163

    Article  PubMed  CAS  Google Scholar 

  • Bellen HJ, O’Kane CJ, Wilson C, Grossniklaus U, Pearson RK et al (1989) P-element-mediated enhancer detection: a versatile method to study development in Drosophila. Genes Dev 3:1288–1300

    Article  PubMed  CAS  Google Scholar 

  • Bier E, Vaessin H, Shepherd S, Lee K, McCall K et al (1989) Searching for pattern and mutation in the Drosophila genome with a P-lacZ vector. Genes Dev 3:1273–1287

    Article  PubMed  CAS  Google Scholar 

  • Biscardi JS, Ishizawar RC, Silva CM, Parsons SJ (2000) Tyrosine kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer. Breast Cancer Res 2:203–210

    Article  PubMed  CAS  Google Scholar 

  • Bonifacino JS (2004) The GGA proteins: adaptors on the move. Nat Rev Mol Cell Biol 5:23–32

    Article  PubMed  CAS  Google Scholar 

  • Brissoni B, Agostini L, Kropf M, Martinon F, Swoboda V et al (2006) Intracellular trafficking of interleukin-1 receptor I requires Tollip. Curr Biol 16:2265–2270

    Article  PubMed  CAS  Google Scholar 

  • Burk O, Klempnauer KH (1999) Myb and Ets transcription factors cooperate at the myb-inducible promoter of the tom-1 gene. Biochim Biophys Acta 1446:243–252

    PubMed  CAS  Google Scholar 

  • Burk O, Worpenberg S, Haenig B, Klempnauer KH (1997) tom-1, a novel v-Myb target gene expressed in AMV- and E26-transformed myelomonocytic cells. EMBO J 16:1371–1380

    Article  PubMed  CAS  Google Scholar 

  • Chenna R, Sugawara H, Koike T, Lopez R, Gibson TJ et al (2003) Multiple sequence alignment with the clustal series of programs. Nucleic Acids Res 31:3497–3500

    Article  PubMed  CAS  Google Scholar 

  • Christopher JA (1998) SPOCK. Texas A&M University, College Station, TX

    Google Scholar 

  • Crawley JN, Paylor R (1997) A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. Horm Behav 31:197–211

    Article  PubMed  CAS  Google Scholar 

  • Fiser A, Sali A (2003) Modeller: generation and refinement of homology-based protein structure models. Methods Enzymol 374:461–491

    Article  PubMed  CAS  Google Scholar 

  • Frampton J, Ramqvist T, Graf T (1996) v-Myb of E26 leukemia virus up-regulates bcl-2 and suppresses apoptosis in myeloid cells. Genes Dev 10:2720–2731

    Article  PubMed  CAS  Google Scholar 

  • Franco M, Furstoss O, Simon V, Benistant C, Hong WJ et al (2006) The adaptor protein Tom1L1 is a negative regulator of Src mitogenic signaling induced by growth factors. Mol Cell Biol 26:1932–1947

    Article  PubMed  CAS  Google Scholar 

  • Girirajan S, Vlangos CN, Szomju BB, Edelman E, Trevors CD et al (2006) Genotype-phenotype correlation in Smith-Magenis syndrome: evidence that multiple genes in 17p11.2 contribute to the clinical spectrum. Genet Med 8:417–427

    Article  PubMed  CAS  Google Scholar 

  • Gossler A, Joyner AL, Rossant J, Skarnes WC (1989) Mouse embryonic stem cells and reporter constructs to detect developmentally regulated genes. Science 244:463–465

    Article  PubMed  CAS  Google Scholar 

  • Grant SG, O’Dell TJ, Karl KA, Stein PL, Soriano P et al (1992) Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science 258:1903–1910

    Article  PubMed  CAS  Google Scholar 

  • Greenberg F, Guzzetta V, Montes de Oca-Luna R, Magenis RE, Smith AC et al (1991) Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2). Am J Hum Genet 49:1207–1218

    PubMed  CAS  Google Scholar 

  • Greenberg F, Lewis RA, Potocki L, Glaze D, Parke J et al (1996) Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2). Am J Med Genet 62:247–254

    Article  PubMed  CAS  Google Scholar 

  • Guo TL, McCay JA, Karrow NA, Brown RD, Musgrove DL et al (2001) Immunotoxicity of sodium bromate in female B6C3F1 mice: a 28-day drinking water study. Drug Chem Toxicol 24:129–149

    Article  PubMed  CAS  Google Scholar 

  • Hall TA (1999) BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser 41:95–98

    CAS  Google Scholar 

  • Hartmann CB, McCoy KL (2004) Gallium arsenide exposure impairs processing of particulate antigen by macrophages: modification of the antigen reverses the functional defect. Life Sci 75:485–498

    Article  PubMed  CAS  Google Scholar 

  • Hogg A, Schirm S, Nakagoshi H, Bartley P, Ishii S et al (1997) Inactivation of a c-Myb/estrogen receptor fusion protein in transformed primary cells leads to granulocyte/macrophage differentiation and down regulation of c-kit but not c-myc or cdc2. Oncogene 15:2885–2898

    Article  PubMed  CAS  Google Scholar 

  • Irwin S (1968) Comprehensive observational assessment: Ia. A systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia 13:222–257

    Article  PubMed  CAS  Google Scholar 

  • Jerne NK, Nordin AA (1963) Plaque formation in agar by single antibody-producing cells. Science 140:405

    Article  Google Scholar 

  • Katoh Y, Shiba Y, Mitsuhashi H, Yanagida Y, Takatsu H et al (2004) Tollip and Tom1 form a complex and recruit ubiquitin-conjugated proteins onto early endosomes. J Biol Chem 279:24435–24443

    Article  PubMed  CAS  Google Scholar 

  • Katoh Y, Imakagura H, Futatsumori M, Nakayama K (2006) Recruitment of clathrin onto endosomes by the Tom1-Tollip complex. Biochem Biophys Res Commun 341:143–149

    Article  PubMed  CAS  Google Scholar 

  • Kirchhausen T (2000) Clathrin. Annu Rev Biochem 69:699–727

    Article  PubMed  CAS  Google Scholar 

  • Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Crystallogr 26:283–291

    Article  CAS  Google Scholar 

  • Lewis TA, Munson AE, McCoy KL (1996) Gallium arsenide selectively suppresses antigen processing by splenic macrophages for CD4+ T cell activation. J Pharmacol Exp Ther 278:1244–1251

    PubMed  CAS  Google Scholar 

  • Li W, Marshall C, Mei L, Dzubow L, Schmults C et al (2005) Srcasm modulates EGF and Src-kinase signaling in keratinocytes. J Biol Chem 280:6036–6046

    Article  PubMed  CAS  Google Scholar 

  • Li W, Marshall C, Mei L, Gelfand J, Seykora JT (2007) Srcasm corrects Fyn-induced epidermal hyperplasia by kinase down-regulation. J Biol Chem 282:1161–1169

    Article  PubMed  CAS  Google Scholar 

  • Lohi O, Lehto VP (1998) VHS domain marks a group of proteins involved in endocytosis and vesicular trafficking. FEBS Lett 440:255–257

    Article  PubMed  CAS  Google Scholar 

  • Lucas RE, Vlangos CN, Das P, Patel PI, Elsea SH (2001) Genomic organisation of the approximately 1.5 Mb Smith-Magenis syndrome critical interval: transcription map, genomic contig, and candidate gene analysis. Eur J Hum Genet 9:892–902

    Article  PubMed  CAS  Google Scholar 

  • Luster MI, Munson AE, Thomas PT, Holsapple MP, Fenters JD et al (1988) Development of a testing battery to assess chemical-induced immunotoxicity: National Toxicology Program’s guidelines for immunotoxicity evaluation in mice. Fundam Appl Toxicol 10:2–19

    Article  PubMed  CAS  Google Scholar 

  • Misra S, Beach BM, Hurley JH (2000) Structure of the VHS domain of human Tom1 (target of myb-1): insights into interactions with proteins and membranes. Biochemistry 39:11282–11290

    Article  PubMed  CAS  Google Scholar 

  • Oh IH, Reddy EP (1999) The myb gene family in cell growth, differentiation and apoptosis. Oncogene 18:3017–3033

    Article  PubMed  CAS  Google Scholar 

  • Park J, Meisler AI, Cartwright CA (1993) c-Yes tyrosine kinase activity in human colon carcinoma. Oncogene 8:2627–2635

    PubMed  CAS  Google Scholar 

  • Potash JB, Buervenich S, Cox NJ, Zandi PP, Akula N et al (2008) Gene-based SNP mapping of a psychotic bipolar affective disorder linkage region on 22q12.3: Association with HMG2L1 and TOM1. Am J Med Genet B Neuropsychiatr Genet 147:59–67

    PubMed  Google Scholar 

  • Puertollano R (2005) Interactions of TOM1L1 with the multivesicular body sorting machinery. J Biol Chem 280:9258–9264

    Article  PubMed  CAS  Google Scholar 

  • Rogers DC, Fisher EM, Brown SD, Peters J, Hunter AJ et al (1997) Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm Genome 8:711–713

    Article  PubMed  CAS  Google Scholar 

  • Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815

    Article  PubMed  CAS  Google Scholar 

  • Seet LF, Hong W (2005) Endofin recruits clathrin to early endosomes via TOM1. J Cell Sci 118:575–587

    Article  PubMed  CAS  Google Scholar 

  • Seet LF, Liu N, Hanson BJ, Hong W (2004) Endofin recruits TOM1 to endosomes. J Biol Chem 279:4670–4679

    Article  PubMed  CAS  Google Scholar 

  • Serafini T, Colamarino SA, Leonardo ED, Wang H, Beddington R et al (1996) Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87:1001–1014

    Article  PubMed  CAS  Google Scholar 

  • Seykora JT, Mei L, Dotto GP, Stein PL (2002) ‘Srcasm: a novel Src activating and signaling molecule. J Biol Chem 277:2812–2822

    Article  PubMed  CAS  Google Scholar 

  • Shiba Y, Katoh Y, Shiba T, Yoshino K, Takatsu H et al (2004) GAT (GGA and Tom1) domain responsible for ubiquitin binding and ubiquitination. J Biol Chem 279:7105–7111

    Article  PubMed  CAS  Google Scholar 

  • Skarnes WC, Auerbach BA, Joyner AL (1992) A gene trap approach in mouse embryonic stem cells: the lacZ reported is activated by splicing, reflects endogenous gene expression, and is mutagenic in mice. Genes Dev 6:903–918

    Article  PubMed  CAS  Google Scholar 

  • Skarnes WC, Moss JE, Hurtley SM, Beddington RS (1995) Capturing genes encoding membrane and secreted proteins important for mouse development. Proc Natl Acad Sci U S A 92:6592–6596

    Article  PubMed  CAS  Google Scholar 

  • Slager RE, Newton TL, Vlangos CN, Finucane B, Elsea SH (2003) Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet 33:466–468

    Article  PubMed  CAS  Google Scholar 

  • Smith AC, McGavran L, Robinson J, Waldstein G, Macfarlane J et al (1986) Interstitial deletion of (17)(p11.2p11.2) in nine patients. Am J Med Genet 24:393–414

    Article  PubMed  CAS  Google Scholar 

  • Stanford WL, Cohn JB, Cordes SP (2001) Gene-trap mutagenesis: past, present and beyond. Nat Rev Genet 2:756–768

    Article  PubMed  CAS  Google Scholar 

  • Stein PL, Lee HM, Rich S, Soriano P (1992) pp59fyn mutant mice display differential signaling in thymocytes and peripheral T cells. Cell 70:41–750

    Article  Google Scholar 

  • Stryke D, Kawamoto M, Huang CC, Johns SJ, King LA et al (2003) BayGenomics: a resource of insertional mutations in mouse embryonic stem cells. Nucleic Acids Res 31:278–281

    Article  PubMed  CAS  Google Scholar 

  • Takatsu H, Katoh Y, Shiba Y, Nakayama K (2001) Golgi-localizing, gamma-adaptin ear homology domain, ADP-ribosylation factor-binding (GGA) proteins interact with acidic dileucine sequences within the cytoplasmic domains of sorting receptors through their Vps27p/Hrs/STAM (VHS) domains. J Biol Chem 276:28541–28545

    Article  PubMed  CAS  Google Scholar 

  • Talbot WS, Hopkins N (2000) Zebrafish mutations and functional analysis of the vertebrate genome. Genes Dev 14:755–762

    PubMed  CAS  Google Scholar 

  • van Dartel M, Hulsebos TJ (2004) Amplification and overexpression of genes in 17p11.2-p12 in osteosarcoma. Cancer Genet Cytogenet 153:77–80

    Article  PubMed  CAS  Google Scholar 

  • Voss AK, Thomas T, Gruss P (1998) Efficiency assessment of the gene trap approach. Dev Dyn 212:171–180

    Article  PubMed  CAS  Google Scholar 

  • Yamakami M, Yokosawa H (2004) Tom1 (target of Myb 1) is a novel negative regulator of interleukin-1- and tumor necrosis factor-induced signaling pathways. Biol Pharm Bull 27:564–566

    Article  PubMed  CAS  Google Scholar 

  • Yang HM, Butterworth L, Munson AE, Meade BJ (2003) Respiratory exposure to diesel exhaust particles decreases the spleen IgM response to a T cell-dependent antigen in female B6C3F1 mice. Toxicol Sci 71:207–216

    Article  PubMed  CAS  Google Scholar 

  • Yeo TT, Yang T, Massa SM, Zhang JS, Honkaniemi J et al (1997) Deficient LAR expression decreases basal forebrain cholinergic neuronal size and hippocampal cholinergic innervation. J Neurosci Res 47:348–360

    Article  PubMed  CAS  Google Scholar 

  • Zarzour W, Kleta R, Frangoul H, Suwannarat P, Jeong A et al (2005) Two novel CHS1 (LYST) mutations: clinical correlations in an infant with Chediak-Higashi syndrome. Mol Genet Metab 85:125–132

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Mario Dance from the VCU Department of Animal Resources for helping with collection of blood samples from mice. They acknowledge Valerie Vinoverski for assistance with GFP studies and Constance B. Hartmann for technical assistance with immunofluorescence staining and flow cytometry. They also thank the Transgenic Animal Model Core at the University of Michigan, the Histopathology Core at Michigan State University, and the Comparative Pathology Lab at UC Davis for mouse tissue and serum studies. This work was supported in part by NIH R01HD38534 (SHE), NIH P50DA05275 (KM), NIH R01ES07199 (KM), the Jeffress Foundation (SHE), the A. D. Williams Trust Fund (KM & SHE), and by resources from Michigan State University and Virginia Commonwealth University.

Author information

Author notes

  1. Paula M. Hauck

    Present address: Molecular Oncology, McGuire Research Institute, Richmond, VA, 23249, USA

  2. Christopher N. Vlangos

    Present address: Department of Pediatrics, University of Michigan, Ann Arbor, MI, 48109, USA

Authors and Affiliations

  1. Department of Human Genetics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Santhosh Girirajan, Stephen Williams & Sarah H. Elsea

  2. Department of Pediatrics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Paula M. Hauck, Christopher N. Vlangos, Barbara B. Szomju, Sara Solaymani-Kohal & Sarah H. Elsea

  3. Department of Medicinal Chemistry and Center for the Study of Biological Complexity, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Philip D. Mosier

  4. Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Kimber L. White Jr.

  5. Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Kathleen McCoy

Authors
  1. Santhosh Girirajan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paula M. Hauck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher N. Vlangos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Barbara B. Szomju
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sara Solaymani-Kohal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Philip D. Mosier
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kimber L. White Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kathleen McCoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sarah H. Elsea
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sarah H. Elsea.

Additional information

S. Girirajan and P. M. Hauck contributed equally to this work.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Girirajan, S., Hauck, P.M., Williams, S. et al. Tom1l2 hypomorphic mice exhibit increased incidence of infections and tumors and abnormal immunologic response. Mamm Genome 19, 246–262 (2008). https://doi.org/10.1007/s00335-008-9100-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-008-9100-6

Keywords

Search

Navigation