Evidence for SH2 domain-containing 5′ -Inositol phosphatase-2 (SHIP2) contributing to a lymphatic dysfunction

Germaine D. Agollah, Manuel L. Gonzalez-Garay, John C. Rasmussen, I. Chih Tan, Melissa B. Aldrich, Chinmay Darne, Caroline E. Fife, Renie Guilliod, Erik A. Maus, Philip D. King, Eva M. Sevick-Muraca

Research output: Contribution to journalArticle

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Abstract

The lymphatic vasculature plays a critical role in a number of disease conditions of increasing prevalence, such as autoimmune disorders, obesity, blood vascular diseases, and cancer metastases. Yet, unlike the blood vasculature, the tools available to interrogate the molecular basis of lymphatic dysfunction/disease have been lacking. More recently, investigators have reported that dysregulation of the PI3K pathway is involved in syndromic human diseases that involve abnormal lymphatic vasculatures, but there have been few compelling results that show the direct association of this molecular pathway with lymphatic dysfunction in humans. Using near-infrared fluorescence lymphatic imaging (NIRFLI) to phenotype and next generation sequencing (NGS) for unbiased genetic discovery in a family with non-syndromic lymphatic disease, we discovered a rare, novel mutation in INPPL1 that encodes the protein SHIP2, which is a negative regulator of the PI3K pathway, to be associated with lymphatic dysfunction in the family. In vitro interrogation shows that SHIP2 is directly associated with impairment of normal lymphatic endothelial cell (LEC) behavior and that SHIP2 associates with receptors that are associated in lymphedema, implicating its direct involvement in the lymphatic vasculature. This work was supported in parts by the National Institutes of Health (NIH) grants R01 HL092923, R01 CA128919, U54 CA136404 and The Texas Star Award (EMS-M) and R01 HL096498 (PDK). GDA acknowledges support from The Schissler Foundation Fellowship for Translational Studies of Common Human Diseases. Flow cytometry measurements were supported in part through a Cancer Prevention and Research Institute of Texas (CPRIT) instrumentation grant (RP110776). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Original languageEnglish (US)
Article numbere112548
JournalPLoS One
Volume9
Issue number11
DOIs
StatePublished - Nov 10 2014

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src Homology Domains
lymphatic diseases
Organized Financing
phosphatidylinositol 3-kinase
Lymphatic Diseases
Phosphatidylinositol 3-Kinases
human diseases
National Institutes of Health
honors and awards
vascular diseases
neoplasms
Lymphedema
Manuscripts
Hematologic Diseases
Optical Imaging
blood
National Institutes of Health (U.S.)
instrumentation
Vascular Diseases
metastasis

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Agollah, G. D., Gonzalez-Garay, M. L., Rasmussen, J. C., Tan, I. C., Aldrich, M. B., Darne, C., ... Sevick-Muraca, E. M. (2014). Evidence for SH2 domain-containing 5′ -Inositol phosphatase-2 (SHIP2) contributing to a lymphatic dysfunction. PLoS One, 9(11), [e112548]. https://doi.org/10.1371/journal.pone.0112548

Evidence for SH2 domain-containing 5′ -Inositol phosphatase-2 (SHIP2) contributing to a lymphatic dysfunction. / Agollah, Germaine D.; Gonzalez-Garay, Manuel L.; Rasmussen, John C.; Tan, I. Chih; Aldrich, Melissa B.; Darne, Chinmay; Fife, Caroline E.; Guilliod, Renie; Maus, Erik A.; King, Philip D.; Sevick-Muraca, Eva M.

In: PLoS One, Vol. 9, No. 11, e112548, 10.11.2014.

Research output: Contribution to journalArticle

Agollah, GD, Gonzalez-Garay, ML, Rasmussen, JC, Tan, IC, Aldrich, MB, Darne, C, Fife, CE, Guilliod, R, Maus, EA, King, PD & Sevick-Muraca, EM 2014, 'Evidence for SH2 domain-containing 5′ -Inositol phosphatase-2 (SHIP2) contributing to a lymphatic dysfunction', PLoS One, vol. 9, no. 11, e112548. https://doi.org/10.1371/journal.pone.0112548
Agollah GD, Gonzalez-Garay ML, Rasmussen JC, Tan IC, Aldrich MB, Darne C et al. Evidence for SH2 domain-containing 5′ -Inositol phosphatase-2 (SHIP2) contributing to a lymphatic dysfunction. PLoS One. 2014 Nov 10;9(11). e112548. https://doi.org/10.1371/journal.pone.0112548
Agollah, Germaine D. ; Gonzalez-Garay, Manuel L. ; Rasmussen, John C. ; Tan, I. Chih ; Aldrich, Melissa B. ; Darne, Chinmay ; Fife, Caroline E. ; Guilliod, Renie ; Maus, Erik A. ; King, Philip D. ; Sevick-Muraca, Eva M. / Evidence for SH2 domain-containing 5′ -Inositol phosphatase-2 (SHIP2) contributing to a lymphatic dysfunction. In: PLoS One. 2014 ; Vol. 9, No. 11.
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