Fes Mediates the IL-4 Activation of Insulin Receptor Substrate-2 and Cellular Proliferation

Abstract

Although Jak kinases are essential for initiating cytokine signaling, the role of other nonreceptor tyrosine kinases in this process remains unclear. We have examined the role of Fes in IL-4 signaling. Examination of Jak1-deficient cell lines demonstrates that Jak1 is required for the activation of Fes by IL-4. Experiments studying signaling molecules activated by IL-4 receptor suggest that IL-4 signaling can be subdivided into Fes-dependent and Fes-independent pathways. Overexpression of kinase-inactive Fes blocks the IL-4 activation of insulin receptor substrate-2, but not STAT6. Fes appears to be a downstream kinase from Jak1/Jak3 in this process. Further examination of downstream signaling demonstrates that kinase-inactive Fes inhibits the recruitment of phosphoinositide 3-kinase to the activated IL-4 receptor complex and decreases the activation of p70S6k kinase in response to IL-4. This inhibition correlates with a decrease in IL-4-induced proliferation. In contrast, mutant Fes does not inhibit the activation of Akt by IL-4. These data demonstrate that signaling pathways activated by IL-4 require different tyrosine kinases. This differential requirement predicts that specific kinase inhibitors may permit the disruption of specific IL-4-induced functions.

Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease

“…Tyrosine phosphorylation of Bcr on Tyr-177 and Tyr-246 by Fes suppresses Bcr serine/threonone kinase activity toward 14-3-3 protein BAP-1 , but induces association with Grb2/mSOS, the Ras guanine nucleotide exchange factor complex (Maru et al, 1995). Signaling downstream of the IL4Ra involves Fes-mediated PI3K recruitment and activation of p70 S6K but not Akt kinase (Jiang et al, 2001). Ras activity as well as activation of the Rho family of small G proteins Rac and Cdc42 are required for ®broblast transformation of myristylated c-Fes (Li and Smithgall, 1998).…”

“…The gp130 signal-transducing subunit forms a part of the IL-6-related cytokine subfamily receptors, and is associated with Fes in the absence of receptor stimulation, while Fes becomes tyrosine phosphorylated after IL-6 stimulation (Matsuda et al, 1995). Fes interacts also with the IL-4Ra subunit and becomes tyrosine phosphorylated by JAK1 upon ligand binding (Izuhara et al, 1994;Jiang et al, 2001). The involvement of Fes in mediating signals downstream of the common b (b c ) subunit, which is part of the IL-3/IL-5/GM-CSF receptor complex, and the erythropoietin (EPO) receptor are however more controversial.…”

“…Identi®ed substrates for the cellular Fes kinase include RasGAP (Hjermstad et al, 1993), Stat3 (Nelson et al, 1998), Cas (Jucker et al, 1997), IRS-2 (Jiang et al, 2001), and Bcr (Maru et al, 1995). Tyrosine phosphorylation of Bcr on Tyr-177 and Tyr-246 by Fes suppresses Bcr serine/threonone kinase activity toward 14-3-3 protein BAP-1 , but induces association with Grb2/mSOS, the Ras guanine nucleotide exchange factor complex (Maru et al, 1995).…”

The tyrosine kinase FES is an essential effector of KITD816V proliferation signal

“…[17][18][19][20]47 In primary erythroid cells, the activation of FES and/or FER downstream of wild-type KIT receptor has been suggested using a dual-specific antibody. 25 Another study showed increased FER phosphorylation in response to SCF in BMMCs.…”

“…FES (feline sarcoma) and FER (FES-related) proteins are the only 2 members of a subfamily of cytoplasmic protein tyrosine kinase. 16 FES has been shown to associate with growth factor and cytokine receptors, [17][18][19][20] which leads to activation of its catalytic activity through tyrosine phosphorylation. The downstream effectors of FES are not clearly characterized, although several studies point to a link between FES and several signaling proteins such as STATs, [21][22][23] the MAP kinases ERK-1 and ERK-2, 24,25 and PI3K.…”