Src-family and Syk Kinases in Activating and Inhibitory Pathways in Innate Immune Cells: Signaling Cross Talk

Abstract

The response of innate immune cells to growth factors, immune complexes, extracellular matrix proteins, cytokines, pathogens, cellular damage and many other stimuli is regulated by a complex net of intracellular signal transduction pathways. The majority of these pathways are either initiated or modulated by Src-family or Syk tyrosine kinases present in innate cells. The Src-family kinases modulate the broadest range of signaling responses, including regulating immunoreceptors, C-type lectins, integrins, G-protein coupled receptors and many others. Src-family kinases also modulate the activity of other kinases, in particular Tec-family members as well as FAK and Pyk2. Syk kinase is required for initiation of signaling involving receptors that utilize immunoreceptor tyrosine activation (ITAM) domains. The Tec kinases play a unique role in Toll-like receptor signaling in innate cells. This chapter will review the major activating and inhibitory signaling pathways regulated by these cytoplasmic tyrosine kinases, illuminating the many examples of signaling crosstalk between pathways.

Immune Complexes Suppress IFN-γ–Induced Responses in Monocytes by Activating Discrete Members of the SRC Kinase Family

“…This is in agreement with the fact that SKF members are generally thought to function upstream of SYK in Fc-dependent pathways (31). Given the number of SRC family kinases, the effects of decreased SRC protein expression by siRNA was perhaps surprising, as the remaining SKF members were unable to fully compensate for it.…”

Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases

“…Next, the ability of library compounds to inhibit FcγRIIA + /γ -/--induced ROS was evaluated. Vehicle control (DMSO) and PP2, an inhibitor of Src family tyrosine kinases known to signal downstream of FcγRs (17,18), served as negative and positive controls, respectively. The screen of 8,483 compounds yielded 84 hits (1% hit rate), defined as those that have an inhibitory potential of ≥95% of PP2 ( Figure 1A).…”

The Src kinases Hck, Fgr, and Lyn activate Abl2/Arg to facilitate IgG-mediated phagocytosis andLeishmaniainfection

“…For example, inhibiting phosphoinositide 3-kinase (PI3K)γ, which can signal though SFKs, Abl and Arg (Bradley and Koleske, 2009), affects Leishmania uptake and impairs the Th2 response (Cummings et al, 2012). Mice lacking SFKs have defects in macrophage recruitment (Park et al, 1999), the respiratory burst (Meng and Lowell, 1998), and B cell and T cell development and signaling (Lowell, 2011). Immunological defects in mice lacking Abl family kinases include defects in B cell and T cell development and signaling, among others; drugs affecting SFK and Abl and Arg also decrease immune cell proliferation (Gu et al, 2007;Huang et al, 2008;Liberatore and Goff, 2009;Silberman et al, 2008;Zipfel et al, 2004).…”