PMID:25694429

Citation	'Llavero, F, Urzelai, B, Osinalde, N, Gálvez, P, Lacerda, HM, Parada, LA and Zugaza, JL (2015) Guanine nucleotide exchange factor αPIX leads to activation of the Rac 1 GTPase/Glycogen phosphorylase pathway in Interleukin (IL)-2-stimulated T cells. J. Biol. Chem. '
Abstract	Recently, we have reported that the active form of Rac 1 GTPase binds to the glycogen phosphorylase muscle isoform (PYGM) and modulates its enzymatic activity leading to T cell proliferation. In the lymphoid system, Rac 1 and in general other small GTPases of the Rho family participate in the signaling cascades that are activated after engagement of the T cell antigen receptor. However, little is known about the IL-2-dependent Rac 1 activator molecules. For the first time, a signaling pathway leading to the activation of Rac 1/PYGM in response to IL-2-stimulated T cell proliferation is described. More specifically, αPIX, a known Guanine Nucleotide Exchange Factor for the small GTPases of the Rho family, preferentially Rac 1, mediates PYGM activation in Kit 225 T cells stimulated with IL-2. Using direct mutagenesis, phosphorylation of αPIX Rho-GEF serines 225 and 488 is required for activation of the Rac 1/PYGM pathway. IL-2-stimulated serine phosphorylation was corroborated in Kit 225 T cells cultures. A parallel pharmacological and genetic approach identified PKCθ as the serine/threonine kinase responsible for αPIX serine phosphorylation. The phosphorylated state of αPIX was required to activate first Rac 1 and subsequently PYGM. These results demonstrate that the IL-2 receptor activation, amongst other early events, leads to activation of PKCθ. In order to activate Rac 1 and consequently PYGM, PKCθ phophorylates αPIX in T cells. The biological significance of this PKCθ/αPIX /Rac 1 GTPase/PYGM signaling pathway seems to be the control of different cellular responses such as migration and proliferation.
Links	PubMed Online version:10.1074/jbc.M114.608414
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:GIT1		GO:0005096: GTPase activator activity	ECO:0000314:		F		αPIX overexpression in the absence of IL-2 resulted in a significant increase of the PYGM activity when compared to control cells (Figure 1A, second empty bar compared to first empty bar). Western blot shows αPIX expression levels As shown in Figure 2 A, in the absence of αPIX (knockdown), IL-2 was unable to stimulate Rac 1 activation	complete CACAO 10697

References

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