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Molecular carcinogenesis
04, 2019;58 (4): 488-499.

NRP-1 interacts with GIPC1 and SYX to activate p38 MAPK signaling and cancer stem cell survival.

Daniel Grun, Gautam Adhikary, Richard L Eckert
Author Information
  1. Daniel Grun: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
  2. Gautam Adhikary: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
  3. Richard L Eckert: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland. ORCID
PMID: 30456845 DOI: 10.1002/mc.22943

Abstract

Epidermal cancer stem cells (ECS cells) comprise a limited population of cells that form aggressive, rapidly growing, and highly vascularized tumors. VEGF-A/NRP-1 signaling is a key driver of the ECS cell phenotype and aggressive tumor formation. However, relatively less is known regarding the downstream events following VEGF-A/NRP-1 interaction. In the present study, we show that VEGF-A/NRP-1, GIPC1, and Syx interact to increase RhoA-dependent p38 MAPK activity to enhance ECS cell spheroid formation, invasion, migration, and angiogenic potential. Inhibition or knockdown of NRP-1, GIPC1 or Syx attenuates RhoA and p38 activity to reduce the ECS cell phenotype, and NRP-1 knockout, or pharmacologic inhibition of VEGF-A/NRP-1 interaction or RhoA activity, reduces p38 MAPK activity and tumor growth. Moreover, expression of wild-type or constitutively-active RhoA, or p38, in NRP1-knockout cells, restores p38 activity and the ECS cell phenotype. These findings suggest that NRP-1 forms a complex with GIPC1 and Syx to activate RhoA/ROCK-dependent p38 activity to enhance the ECS cell phenotype and tumor formation.

Keywords

GIPC1 NRP-1 Syx angiogenesis cancer stem cells p38 MAPK squamous cell carcinoma vascularization

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Grants

  1. CA131074/NIH HHS
  2. CA184027/NIH HHS
  3. R01 CA184027/NCI NIH HHS
  4. R01 CA131074/NCI NIH HHS
  5. R01 CA211909/NCI NIH HHS

MeSH Term

Adaptor Proteins, Signal Transducing
Animals
Apoptosis
Biomarkers, Tumor
Cell Movement
Cell Proliferation
Epidermis
Gene Expression Regulation, Neoplastic
Guanine Nucleotide Exchange Factors
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Neoplastic Stem Cells
Neovascularization, Pathologic
Neuropilin-1
Signal Transduction
Skin Neoplasms
Spheroids, Cellular
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
p38 Mitogen-Activated Protein Kinases
rhoA GTP-Binding Protein

Chemicals

Adaptor Proteins, Signal Transducing
Biomarkers, Tumor
GIPC1 protein, human
Guanine Nucleotide Exchange Factors
NRP1 protein, human
PLEKHG5 protein, human
RHOA protein, human
Neuropilin-1
p38 Mitogen-Activated Protein Kinases
rhoA GTP-Binding Protein
Journal Article Research Support, N.I.H., Extramural

Word Cloud

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