title: PI3-kinase γ promotes Rap1a-mediated activation of myeloid cell integrin α4β1, leading to tumor inflammation and growth.
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.
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Schmid
authors.forename: Irene
authors.initials: I
authors.lastname: Franco
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Kang
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Quilliam
authors.forename: Judith A
authors.initials: JA
authors.lastname: Varner
mesh_terms: D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D039041:Integrin alpha4beta1 / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D039041:Integrin alpha4beta1; D008024:Ligands; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D051966:Phospholipase C gamma; D020827:rap1 GTP-Binding Proteins
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