Akt2 is required for macrophage chemotaxis

Abstract

Tumor-associated macrophages play an important role in tumorigenesis and metastasis. Trafficking of macrophages to the proximity of tumors is mediated by CSF-1, a growth factor. In this study, we investigated the role of PKB/Akt in CSF-1-induced macrophage migration. Disruption of Akt2 expression by small interference RNA impaired chemotaxis of both THP-1 cells and mouse peritoneal macrophages. Phosphorylation of PKCf, an essential component in chemotaxis signaling pathway, was reduced. LIMK/Cofilin, downstream of PKCf, regulated cytoskeleton rearrangement during cell migration. Disruption of Akt2 expression inhibited CSF-1-induced LIMK/Cofilin phosphorylation, which contributed to defects in actin polymerization and chemotaxis. Furthermore, MCP-1, a chemokine, -induced macrophage chemotaxis was also impaired. Taken together, our results demonstrated that Akt2 plays an essential role in both CSF-1-and chemokine-induced chemotaxis of macrophages.Key words: Chemokine . CSF-1 . Metastasis . Tumor-associated macrophages IntroductionChronicle inflammation promotes, sometimes even induces, tumorigenesis [1,2]. Tumor attracts macrophages and induces their differentiation by secreting . In comparison with conventional macrophages, tumor-associated macrophage (TAM) cells exhibit poor antigen-presenting capability, produce factors that suppress T-cell proliferation and activity, and are generally better adapted to scavenging debris, promoting angiogenesis, repairing and remodeling wounded/damaged tissues [3]. Recent studies show that TAM cells also play an essential role in inducing invasion and metastasis of breast tumors [4,5]. TAM cells secrets EGF to induce the proliferation and invasion of surrounding tissues by tumor cells [6]. Eventually, migratory cancer cells follow EGF gradient, enter the circulation, and spread throughout the body. Depletion of macrophages effectively blocked metastasis in a mouse model [7]. Thus, disrupt of TAM function will provide a novel approach to develop anti-cancer therapies.Recruitment of macrophages to the proximity of tumors was mediated by CSF-1, a growth factor, secreted by tumor cells [6]. CSF-1 also stimulates the proliferation, differentiation, and survival of macrophages [8]. Macrophages stimulated with CSF-1 show immediate cell polarization, actin reorganization, and migration to the CSF-1 secreting tumor cells [9]. Extensive studies have revealed the molecular mechanism of chemokine receptor, a subfamily of G-protein-coupled receptors, -mediated leukocyte trafficking during inflammation [10,11]. However, the signal transduction pathway that regulates CSF-1-induced macrophage migration is still largely unknown. Investigating molecular mechanism of CSF-1-mediated macrophage chemotaxis will provide new insights to block the formation and accumulation of TAM cells.The Akt/PKB family, Akt1, 2, and 3, plays a critical role in regulating cell growth, proliferation, survival, and metabolism [12,13]. Akt1 and 2 are expressed in most cell types and tissues 894while Akt3 shows a more r...

Plasmin Triggers Chemotaxis of Monocyte-Derived Dendritic Cells Through an Akt2-Dependent Pathway and Promotes a T-Helper Type-1 Response

“…36 In contrast to plasmin, lipopolysaccharide or CD40 stimulation of murine bone marrow-derived DC activates almost exclusively Akt1, which plays a major role for DC survival and maturation. 37 However, the selective Akt2 stimulation associated with the plasmin-induced chemotactic response is in line with a recent study 38 showing that Akt2 is essential for the colony-stimulating factor-1-induced and the MCP-1-induced chemotaxis in mouse peritoneal macrophages.…”

CSF-1 Receptor Signaling in Myeloid Cells

“…Although studies in SHIP 2/2 macrophages implicate Vav proteins (Vedham et al 2005), studies in single or tripledeficient Vav1/2/3 2/2 primary macrophages indicate that they are not required (Wells et al 2005;Bhavsar et al 2009). In contrast, the PI3K/Akt pathway plays a central role in CSF-1R-induced chemotaxis (Sampaio et al 2011), via phosphorylation of PKC-z and LIMK/Cofilin (Zhang et al 2009). Two adaptor proteins, Lnk and STAP-2, suppress Akt activation and inhibit CSF-1-induced macrophage migration (Ikeda et al 2007;Gueller et al 2010).…”

PKB/Akt-dependent regulation of inflammation in cancer

“…Although members of the SWI/SNF chromatin-remodeling complex have been shown to interact with and be phosphorylated by PKB [109], a direct contribution of PKB in the context of SWI/SNF mediated CSF-1 expression is still missing. Nonetheless, PKB has been shown to be required for macrophage chemotaxis in response to both CSF-1 and CCL2 [110].…”