Interleukin-2 Triggers a Novel Phosphatidylinositol 3-Kinase-Dependent MEK Activation Pathway

Abstract

, MEK, but did not inhibit activation of Raf, the canonical upstream activator of MEK. These results suggest that a novel wortmanninsensitive activation pathway regulates MEK and MAP kinase in IL-2-stimulated T lymphocytes.The interaction of a resting T cell with appropriately presented antigen initiates cell cycle entry (G 0 -to G 1 -phase transition) and the expression of high-affinity interleukin-2 (IL-2) receptors (IL-2R). The binding of IL-2 to the IL-2R then elicits G 1 -to S-phase progression and commits the cell to traverse the remainder of the cell cycle. The high-affinity IL-2R is minimally composed of an IL-2R␣ (p55), IL-2R␤ (p70), and ␥ c (p64) subunit (57). However, heterodimerization of the IL-2R␤ and ␥ c intracellular domains is sufficient to trigger the mitogenic response (42,44).Although the IL-2R subunits exhibit no intrinsic protein tyrosine kinase (PTK) activity, IL-2-induced PTK activation is requisite for proliferation (47). The IL-2R␤ chain is physically and functionally coupled to the Src-family PTKs, Lck (20,21), Fyn (25,26,36), and Lyn (59). Additionally, the newly discovered JAK family PTKs, JAK1 and JAK3, are also activated by IL-2 (22, 65). Ligand-induced PTK activation elicits the downstream activation of multiple signaling components, one of which is the well-defined Ras/MAP kinase pathway. The Ras/ MAP kinase pathway comprises a set of ubiquitous and highly conserved molecules that orchestrate the delivery of signals from the cell membrane to the nucleus (reviewed in reference 34). IL-2R ligation appears to regulate Ras via the tyrosine phosphorylation of the adaptor protein, Shc (8,50,70). Tyrosine-phosphorylated Shc then associates with the Src homology 2 (SH2) domain of the adaptor protein, Grb2 (2, 70), which is constitutively bound to the mammalian homolog of the Ras guanine-nucleotide exchange protein, Son of Sevenless (SOS) (18, 31). Complex formation results in the SOS-catalyzed exchange of GDP for GTP on Ras, with the concomitant activation of Ras (17,54). Activated Ras interacts with the regulatory N terminus of the serine-threonine kinase, Raf (38,62,64,68), localizing Raf to the membrane and providing a requisite signal for Raf activation (30, 55). Activated Raf then initiates a protein kinase cascade by phosphorylating and activating MEK (33), which, in turn, phosphorylates and activates MAP kinase (14,33,43).The studies cited above define a linear signal transduction pathway leading to MAP kinase activation. However, recent data suggest that other signaling events also regulate the activity of this signaling cascade (7,28,67,69). In addition to activating the Ras pathway, IL-2 also activates phosphatidylinositol 3-kinase (PI3-K) (4, 35, 51) via a Src family kinasedependent mechanism (25). This heterodimeric lipid kinase comprises an 85-kDa regulatory subunit and a 110-kDa catalytic subunit, which phosphorylate phosphatidylinositol at the D-3 hydroxyl of the inositol ring (reviewed in reference 15). PI3-K activation correlates closely with tyrosine kinase growth facto...

Constitutive PI3-K activity is essential for proliferation, but not survival, of Theileria parva-transformed B cells

“…Host cell proliferation can be blocked by pharmacological inhibition of PI3-K In many different systems, PI3-K activity has been linked to proliferative pathways via activation of MAP kinase (Karnitz et al, 1995), p70S6K (Alessi et al, 1997), c-Jun N-terminal kinase (JNK) (Klippel et al, 1996), PKB or proteins of the PKC family (Akimoto et al, 1996;Sontag et al, 1997). To examine whether the continuous proliferation of T. parva-infected B cells depends on PI3-K activity, we took advantage of two unrelated PI3-K inhibitors, LY294002 and wortmannin.…”

ATM, a DNA damage-inducible kinase, contributes to activation by high NaCl of the transcription factor TonEBP/OREBP

“…These results are consistent with a role for ATM in hypertonicity-induced activation of TonEBP͞ OREBP. However, because wortmannin also inhibits other phosphatidylinositol kinase kinases, including DNA-PK and phosphatidylinositol 3-kinase (23,24), additional experiments were required to confirm the role of ATM.…”

Calcium/Calmodulin-dependent Protein Kinase II Binds to Raf-1 and Modulates Integrin-stimulated ERK Activation

“…Activation of PKC contributes to Raf/Erk-1/2 activation in response to cyclic pressure-induced strain in endothelial cells (36). Ras-mediated activation of Erk-1/2, either by insulin, insulin like-growth factor I, interleukin-8 and -2, platelet-derived growth factor, vasopressin, T cell receptor, and adrenergic receptors is increased by Raf-1 co-activation by PI3-K (37)(38)(39)(40)(41)(42)(43). Although a direct effect of CaM on Raf-1 activity has been proposed in response to epidermal growth factor receptor activation, a direct CaMKII/Raf-1 interaction has not yet been described (21,22,44).…”