Regulation of mTOR Signaling by Semaphorin 3F-Neuropilin 2 Interactions In Vitro and In Vivo

Hironao Nakayama; Sarah Bruneau; Nora Kochupurakkal; Silvia Coma; David M Briscoe; Michael Klagsbrun

doi:10.1038/srep11789

Regulation of mTOR Signaling by Semaphorin 3F-Neuropilin 2 Interactions In Vitro and In Vivo

Sci Rep. 2015 Jul 9:5:11789. doi: 10.1038/srep11789.

Authors

Hironao Nakayama¹, Sarah Bruneau², Nora Kochupurakkal², Silvia Coma³, David M Briscoe², Michael Klagsbrun⁴

Affiliations

¹ 1] Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115 [2] Transplant Research Program, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115 [3] Department of Surgery, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115 [4] Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Ehime 791-0295, Japan.
² 1] Transplant Research Program, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115 [2] Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115.
³ 1] Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115 [2] Department of Surgery, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115.
⁴ 1] Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115 [2] Department of Surgery, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115 [3] Department of Pathology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115.

Abstract

Semaphorin 3F (SEMA3F) provides neuronal guidance cues via its ability to bind neuropilin 2 (NRP2) and Plexin A family molecules. Recent studies indicate that SEMA3F has biological effects in other cell types, however its mechanism(s) of function is poorly understood. Here, we analyze SEMA3F-NRP2 signaling responses in human endothelial, T cell and tumor cells using phosphokinase arrays, immunoprecipitation and Western blot analyses. Consistently, SEMA3F inhibits PI-3K and Akt activity, and responses are associated with the disruption of mTOR/rictor assembly and mTOR-dependent activation of the RhoA GTPase. We also find that the expression of vascular endothelial growth factor, as well as mTOR-inducible cellular activation responses and cytoskeleton stability are inhibited by SEMA3F-NRP2 interactions in vitro. In vivo, local and systemic overproduction of SEMA3F reduces tumor growth in NRP2-expressing xenografts. Taken together, SEMA3F regulates mTOR signaling in diverse human cell types, suggesting that it has broad therapeutic implications.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Actins / metabolism
Animals
Cell Line, Tumor
Disease Models, Animal
Heterografts
Humans
Hypoxia / metabolism
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Models, Biological
Multiprotein Complexes / metabolism
Neoplasms / genetics
Neoplasms / metabolism
Neoplasms / pathology
Neovascularization, Pathologic / metabolism
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Neuropilin-2 / metabolism*
Phosphorylation
Protein Binding
Proto-Oncogene Proteins c-akt / metabolism
Ribosomal Protein S6 Kinases / metabolism
Signal Transduction*
TOR Serine-Threonine Kinases / metabolism*
Tumor Burden
Vascular Endothelial Growth Factor A / metabolism

Substances

Actins
Membrane Proteins
Multiprotein Complexes
Nerve Tissue Proteins
Neuropilin-2
SEMA3F protein, human
Vascular Endothelial Growth Factor A
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases
TOR Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding