Guanine Nucleotide Exchange Factor αPIX Leads to Activation of the Rac 1 GTPase/Glycogen Phosphorylase Pathway in Interleukin (IL)-2-stimulated T Cells

Llavero, Francisco; Urzelai, Bakarne; Osinalde, Nerea; Gálvez, Patrícia; Lacerda, Hadriano M.; Parada, Luis Antonio; Zugaza, José L.

doi:10.1074/jbc.m114.608414

Cited by 22 publications

(26 citation statements)

References 63 publications

(74 reference statements)

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“…Loss of GIT2 also mislocalizes the direction of superoxide release (Mazaki et al, 2006). In T-cells, IL2 activates Rac1 through PKCθ-mediated phosphorylation of α-PIX at Ser225 and Ser488 (Llavero et al, 2015). In rat basophilic leukemia cells, depletion of GIT1 but not GIT2 alters chemokine-directed cell migration (Gavina et al, 2010).…”

Section: Functions In the Immune Systemmentioning

confidence: 99%

Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

Weiyuan

Premont

2016

Journal of Cell Science

100

130

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The GIT proteins, GIT1 and GIT2, are GTPase-activating proteins (inactivators) for the ADP-ribosylation factor (Arf ) small GTP-binding proteins, and function to limit the activity of Arf proteins. The PIX proteins, α-PIX and β-PIX (also known as ARHGEF6 and ARHGEF7, respectively), are guanine nucleotide exchange factors (activators) for the Rho family small GTP-binding protein family members Rac1 and Cdc42. Through their multi-domain structures, GIT and PIX proteins can also function as signaling scaffolds by binding to numerous protein partners. Importantly, the constitutive association of GIT and PIX proteins into oligomeric GIT-PIX complexes allows these two proteins to function together as subunits of a larger structure that coordinates two distinct small GTP-binding protein pathways and serves as multivalent scaffold for the partners of both constituent subunits. Studies have revealed the involvement of GIT and PIX proteins, and of the GIT-PIX complex, in numerous fundamental cellular processes through a wide variety of mechanisms, pathways and signaling partners. In this Commentary, we discuss recent findings in key physiological systems that exemplify current understanding of the function of this important regulatory complex. Further, we draw attention to gaps in crucial information that remain to be filled to allow a better understanding of the many roles of the GIT-PIX complex in health and disease.

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Section: Functions In the Immune Systemmentioning

confidence: 99%

Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

Weiyuan

Premont

2016

Journal of Cell Science

100

130

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“…In this way, they control a wide variety of cellular processes among which are the actin cytoskeleton reorganization, the formation of integrin complexes, cell adhesion, gene transcription, cell cycle progression, and cell proliferation [4,5,[32][33][34]. In fact, the control of CDKs by the activation of the growth factor-dependent Ras/MAP kinase pathway [35] , were maintained in the serum-free medium for 24 h and stained with PKH26.…”

Section: Discussionmentioning

confidence: 99%

“…This molecular structure and its potential to establish intermolecular interactions result in a complex and flexible platform for both recognition and processing information as well as the transduction of signals to the cell cytosol and the nucleus. B lymphocytes may be maintained in a quiescent state and stimulation of BCR leads to potent activation of signalling molecules, such as the small GTPases of the Ras superfamily [2][3][4][5] mediating the activation of intracellular signalling cascades [2][3][4][5][6][7][8][9]. Briefly, BCR stimulates the activity of both the Syk [10,11] and the Src family of protein tyrosine kinases [12] leading to the activation of the B cell signalosome, which includes the adapter protein BLNK (B cell linker-protein), Bruton's tyrosine kinase (BTK) and phospholipase Cc2 (PLCc2) [13,14].…”

Section: Introductionmentioning

confidence: 99%

Rac1/p21‐activated kinase pathway controls retinoblastoma protein phosphorylation and E2F transcription factor activation in B lymphocytes

et al. 2016

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Small GTPases of the Ras superfamily are capable of activating E2F-dependent transcription leading to cell proliferation, but the molecular mechanisms are poorly understood. In this study, using immortalized chicken DT40 B cell lines to investigate the role of the Vav/Rac signalling cascade on B cell proliferation, it is shown that the proliferative response triggered by B cell receptor activation is dramatically reduced in the absence of Vav3 expression. Analysis of this proliferative defect shows that in the absence of Vav3 expression, retinoblastoma protein (RB) phosphorylation and the subsequent E2F activation do not take place. By combining pharmacological and genetic approaches, phosphatidylinositol-3-kinase and phospholipase Cc2 (PLCc2) were identified as the key regulatory signalling molecules upstream of the Vav3/Rac pathway leading to RB phosphorylation and E2F transcription factor activation. Additionally, vav3À/À and plcc2 À/À DT40 B cells were not able to activate the RB-E2F complex wild-type phenotype when these genetically modified cells were transfected with constitutively active forms of RhoA or Cdc42. However, when these knockout cells were transfected with different constitutively active versions of PLCc, Vav or Rac1, not only activation of the RB-E2F complex wild-type phenotype was recovered but also the cellular proliferation. Furthermore, by evaluating the effect of two known effector mutants of Rac1 (Rac1 Q61L/F37A and Rac1), the RB-E2F complex activation dependency on p21-activated kinase (PAK) and protein kinase Ce (PKCe) activities was established, being independent of both actin cytoskeleton reorganization and Ras activity. These results suggest that PAK1 and PKCe may be potential therapeutic targets to stop uncontrolled B cell proliferation mediated by the Vav/Rac pathway.Abbreviations BAPTA/AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N 0 ,N 0 -tetraacetic acid tetrakis(acetoxymethyl ester); BCR, B cell receptor; CDK, cyclindependent kinase; DAG, diacylglycerol; GEF, guanine nucleotide exchange factor; PAK, p21-activated kinase; PI3K, phosphatidylinositol-3-kinase; PKC, protein kinase C; PKD, protein kinase D; PLC, phospholipase C; PMA, phorbol 12-myristate 13-acetate; RasGRP, RAS guanyl releasing protein; RB, retinoblastoma protein.

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“…Genetic approaches such as site-directed mutagenesis have greatly expanded our knowledge about biological role of the site specific phosphorylations occurring in proteins [22][23][24]. The increasing number of commercially available phosphosite-specific antibodies also allows detecting relatively easily whether a protein is phosphorylated or not on a certain residue that has been previously described.…”

Section: Introductionmentioning

confidence: 99%

Targeted mass spectrometry: An emerging powerful approach to unblock the bottleneck in phosphoproteomics

Osinalde

Aloria

Omaetxebarria

et al. 2017

Journal of Chromatography B

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Guanine Nucleotide Exchange Factor αPIX Leads to Activation of the Rac 1 GTPase/Glycogen Phosphorylase Pathway in Interleukin (IL)-2-stimulated T Cells

Cited by 22 publications

References 63 publications

Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

Rac1/p21‐activated kinase pathway controls retinoblastoma protein phosphorylation and E2F transcription factor activation in B lymphocytes

Targeted mass spectrometry: An emerging powerful approach to unblock the bottleneck in phosphoproteomics

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