PI3-Kinase γ Promotes Rap1a-Mediated Activation of Myeloid Cell Integrin α4β1, Leading to Tumor Inflammation and Growth

Michael C. Schmid, Irene Franco, Sang Won Kang, Emilio Hirsch, Lawrence Quilliam, Judith A. Varner

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Tumor inflammation, the recruitment of myeloid lineage cells into the tumor microenvironment, promotes angiogenesis, immunosuppression and metastasis. CD11b+Gr1lo monocytic lineage cells and CD11b+Gr1hi granulocytic lineage cells are recruited from the circulation by tumor-derived chemoattractants, which stimulate PI3-kinase γ (PI3Kγ)-mediated integrin α4 activation and extravasation. We show here that PI3Kγ activates PLCγ, leading to RasGrp/CalDAG-GEF-I&II mediated, Rap1a-dependent activation of integrin α4β1, extravasation of monocytes and granulocytes, and inflammation-associated tumor progression. Genetic depletion of PLCγ, CalDAG-GEFI or II, Rap1a, or the Rap1 effector RIAM was sufficient to prevent integrin α4 activation by chemoattractants or activated PI3Kγ (p110γCAAX), while activated Rap (RapV12) promoted constitutive integrin activation and cell adhesion that could only be blocked by inhibition of RIAM or integrin α4β1. Similar to blockade of PI3Kγ or integrin α4β1, blockade of Rap1a suppressed both the recruitment of monocytes and granulocytes to tumors and tumor progression. These results demonstrate critical roles for a PI3Kγ-Rap1a-dependent pathway in integrin activation during tumor inflammation and suggest novel avenues for cancer therapy.

Original languageEnglish
Article numbere60226
JournalPLoS One
Volume8
Issue number4
DOIs
StatePublished - Apr 2 2013

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integrins
Myeloid Cells
Phosphatidylinositol 3-Kinases
Integrins
Tumors
phosphotransferases (kinases)
inflammation
Chemical activation
Inflammation
neoplasms
Growth
Neoplasms
cells
Chemotactic Factors
Programmable logic controllers
chemoattractants
Granulocytes
granulocytes
Monocytes
monocytes

ASJC Scopus subject areas

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

Cite this

PI3-Kinase γ Promotes Rap1a-Mediated Activation of Myeloid Cell Integrin α4β1, Leading to Tumor Inflammation and Growth. / Schmid, Michael C.; Franco, Irene; Kang, Sang Won; Hirsch, Emilio; Quilliam, Lawrence; Varner, Judith A.

In: PLoS One, Vol. 8, No. 4, e60226, 02.04.2013.

Research output: Contribution to journalArticle

Schmid, Michael C. ; Franco, Irene ; Kang, Sang Won ; Hirsch, Emilio ; Quilliam, Lawrence ; Varner, Judith A. / PI3-Kinase γ Promotes Rap1a-Mediated Activation of Myeloid Cell Integrin α4β1, Leading to Tumor Inflammation and Growth. In: PLoS One. 2013 ; Vol. 8, No. 4.
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