Association of RACK1 and PKCβ with the common β-chain of the IL-5/IL-3/GM-CSF receptor

Geijsen, Niels; Spaargaren, Marcel; Raaijmakers, J. A. M.; Lammers, Jan‐Willem J.; Koenderman, Leo; Coffer, Paul J.

doi:10.1038/sj.onc.1202896

Cited by 87 publications

(69 citation statements)

References 34 publications

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“…To further assess the validity of our GST-PAKcrib pull-down assay, we treated PMNs with fMLP (10 Ϫ7 M, 1 min) and found that this substance increased the activity of Cdc42 (196 Ϯ 22% over controls; n ϭ 4, p Ͻ 0.01), Rac1 (160 Ϯ 21% over controls; n ϭ 4, p Ͻ 0.05) and Rac2 (400 Ϯ 106% over controls; n ϭ 4, p Ͻ 0.05), which agrees with the results reported by other investigators (33,35,36). Thus, these findings show that the fMLP receptor and the ␤ 2 integrins collaborate in regulation of Cdc42 but oppose each other in the regulation of Rac GTPases.…”

Section: ␤ 2 Integrin-mediated Regulation Of Rac and Cdc42supporting

confidence: 82%

Down-regulation of Rac Activity during β2 Integrin-mediated Adhesion of Human Neutrophils

Dib

Melander

Axelsson

et al. 2003

Journal of Biological Chemistry

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In human neutrophils, ␤ 2 integrin engagement mediated a decrease in GTP-bound Rac1 and Rac2. Pretreatment of neutrophils with LY294002 or PP1 (inhibiting phosphatidylinositol 3-kinase (PI 3-kinase) and Src kinases, respectively) partly reversed the ␤ 2 integrin-induced down-regulation of Rac activities. In contrast, ␤ 2 integrins induced stimulation of Cdc42 that was independent of Src family members. The PI 3-kinase dependence of the ␤ 2 integrin-mediated decrease in GTP-bound Rac could be explained by an enhanced Rac-GAP activity, since this activity was blocked by LY204002, whereas PP1 only had a minor effect. The fact that only Rac1 but not Rac2 (the dominating Rac) redistributed to the detergent-insoluble fraction and that it was independent of GTP loading excludes the possibility that down-regulation of Rac activities was due to depletion of GTPbound Rac from the detergent-soluble fraction. The ␤ 2 integrin-triggered relocalization of Rac1 to the cytoskeleton was enabled by a PI 3-kinase-induced dissociation of Rac1 from LyGDI. The dissociations of Rac1 and Rac2 from LyGDI also explained the PI 3-kinase-dependent translocations of Rac GTPases to the plasma membrane. However, these accumulations of Rac in the membrane, as well as that of p47 phox and p67 phox , were also regulated by Src tyrosine kinases. Inasmuch as Rac GTPases are part of the NADPH oxidase and the respiratory burst is elicited in neutrophils adherent by ␤ 2 integrins, our results indicate that activation of the NADPH oxidase does not depend on the levels of Rac-GTP but instead requires a ␤ 2 integrin-induced targeting of the Rac GTPases as well as p47 phox and p67 phox to the plasma membrane.

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Section: ␤ 2 Integrin-mediated Regulation Of Rac and Cdc42supporting

confidence: 82%

Down-regulation of Rac Activity during β2 Integrin-mediated Adhesion of Human Neutrophils

Dib

Melander

Axelsson

et al. 2003

Journal of Biological Chemistry

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“…In a similar manner to chemokines, the chemoattractant fMLP signals via GPCRs and has been demonstrated to induce Rac activation in neutrophils (16,27,47,48). Many studies suggest a critical role of PI3K in the regulation of Rac GTPase (49); however, contradictory findings were reported concerning the PI3K dependence of fMLP-stimulated Rac activation (27,47,48,50).…”

Section: Pi3k␥-dependent and Pi3k-independent G I -Mediated Activatiomentioning

confidence: 85%

“…Many studies suggest a critical role of PI3K in the regulation of Rac GTPase (49); however, contradictory findings were reported concerning the PI3K dependence of fMLP-stimulated Rac activation (27,47,48,50). Rac activation seemed surprisingly independent of PI3K␥, because neutrophils pooled from PI3K␥Ϫ/Ϫ mice showed no obvious defect of Rac activation after fMLP stimulation for 5 s (16).…”

Section: Pi3k␥-dependent and Pi3k-independent G I -Mediated Activatiomentioning

confidence: 99%

“…We used differentiated adherent macrophages in our study. There are indeed reports that human and murine neutrophils activated Rac independently of PI3K (48) or PI3K␥ (16) in response to fMLP stimulation, whereas transfected COS-7 cells that express the fMLP receptor showed PI3K␥-dependent activation of Rac (50).…”

Section: Pi3k␥-dependent and Pi3k-independent G I -Mediated Activatiomentioning

confidence: 99%

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Involvement of Phosphoinositide 3-Kinase γ, Rac, and PAK Signaling in Chemokine-induced Macrophage Migration

Weiss-Haljiti

Pasquali

et al. 2004

Journal of Biological Chemistry

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In macrophages, chemotactic stimuli cause the activation of Rac and PAK, but little is known about the signaling pathways involved and their role in chemotactic gradient sensing. Herein, we report that in macrophages, the chemokine RANTES (regulated on activation normal T cell expressed and secreted)/CCL5 activates the small GTPase Rac and its downstream target PAK2 within seconds. This response depends on G i activation and largely on the subsequent triggering of phosphoinositide 3-kinase ␥ (PI3K␥) and Rac. Retroviral transduction of tagged Rac1 and -2 indicates that RAN-TES/CCL5-mediated activation of PI3K␥ triggers Rac1 but not Rac2. In agreement, silencing of Rac1 by shRNA blocks PAK2 activity and inhibits RANTES/CCL5-induced macrophage polarization and directional migration. On the other hand, the tyrosine kinase receptor agonist CSF-1 activates PAK2 independently of PI3K␥ and Rac. Our results thus demonstrate a chemokinespecific signaling pathway in which G i and PI3K␥ coordinate to drive Rac1 and PAK2 activation that eventually controls the chemotactic response.Rac1, Rac2, and Rac3 constitute a subfamily of the Rho family of monomeric GTPases and cycle between active GTP-bound (Rac GTP ) and inactive GDP-bound (Rac GDP ) states (1-3). Activation is accomplished by guanine-nucleotide exchange factors (GEFs), 1 which catalyze GDP dissociation (4), and inactivation by GTPase-activating proteins, which increase the intrinsic GTPase activity (5). Rho GTPases integrate signals from cellular receptors and membrane components to regulate the cytoskeleton dynamics required for cell locomotion during chemotaxis, phagocytosis, and many other cellular responses (2, 6).Leukocyte chemotaxis toward sites of inflammation (7) is primarily mediated by chemokine signaling. RANTES CCL5 is a disease-relevant and potent chemoattractant for macrophages. Moreover, it has been shown that RANTES-mediated T-cell activation and chemotaxis requires Rho GTPase activity (8,9). RANTES is a member of the CC-subfamily of chemokines and activates the seven-transmembrane CC-chemokine receptors CCR1, CCR3, CCR4, and CCR5, which are coupled to pertussis toxin sensitive heterotrimeric G i␣ proteins (10). PI3K was identified as a target of these G-protein-coupled chemokine receptors because chemotaxis and polarization of T cells could be inhibited by isoform non-selective class I PI3K inhibitors, such as LY294002 (11). All class I PI3Ks are heterodimers consisting of a 110-kDa (p110) catalytic subunit and an 85-(p85) or 101-kDa (p101) regulatory subunit (12). The two catalytic subunits p110␣ and -␤ are ubiquitously expressed, whereas p110␥ and -␦ expression is largely confined to leukocytes. In addition to their characteristic expression, PI3Ks are differentially regulated by GPCRs and receptor tyrosine kinases (RTKs) (13). RTKs have been shown to activate p110␣, -␤, and -␦ via the p85 regulatory subunit (class I A: PI3K-␣, -␤, and -␦). In contrast, it has been shown that regulation of p110␥ (class I B: PI3K␥) is mediated via the p101 adapter, ...

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“…The physical interaction between RACK1 and integrin b subunit or Src is dependent on the stimulation of cells with phorbol ester PMA (Liliental and Chang, 1998;Chang et al, 2001), suggesting that PKC activation is required for the above interaction. On the other hand, the interaction of RACK1 with the common b-chain of the cytokine receptors, cAMPspecific phosphodiesterase isoform PDE4D5 or BZLF1 is constitutive and unaffected in the presence of PMA (Geijsen et al, 1999;Yarwood et al, 1999;Baumann et al, 2000). Thus, RACK1 appears to be associated with cellular proteins in a manner dependent or independent on the PKC activation.…”

Section: Discussionmentioning

confidence: 86%

Function of p73, not of p53, is inhibited by the physical interaction with RACK1 and its inhibitory effect is counteracted by pRB

et al. 2003

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The newly identified p53-related gene, p73, encodes a nuclear transcription factor. Unlike p53, p73 has various isoforms with different NH 2 -and COOH-terminal tails. p73a with the longest COOH-terminal extension is most abundantly expressed in many tissues and cells among those splicing isoforms of p73 and the COOH-terminal region appears to have an autoregulatory function. To isolate and characterize the cellular protein(s) that interacts with the unique COOH-terminal region of p73a, we employed a yeast two-hybrid screen with a human fetal brain and 293 cell cDNA libraries. We identified the receptor for activated C kinase (RACK1) as a new member of p73a-binding proteins. The interaction was confirmed by coimmunoprecipitation experiments, whereas RACK1 did not interact with p53 or p73b. Ectopic overexpression of RACK1 in SAOS-2 cells reduced the p73a-mediated transcription from the p53/ p73-responsive promoters, and inhibited the p73a-dependent apoptosis. On the other hand, the p53-dependent transcriptional activation as well as apoptosis was unaffected in the presence of RACK1. Furthermore, we found that pRB physically bound to RACK1, and repressed the RACK1-dependent inhibition of p73a. Taken together, our observations suggest that pRB diminishes the RACK1-mediated inhibition of p73a activity through the interaction with RACK1.

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Association of RACK1 and PKCβ with the common β-chain of the IL-5/IL-3/GM-CSF receptor

Cited by 87 publications

References 34 publications

Down-regulation of Rac Activity during β2 Integrin-mediated Adhesion of Human Neutrophils

Down-regulation of Rac Activity during β2 Integrin-mediated Adhesion of Human Neutrophils

Involvement of Phosphoinositide 3-Kinase γ, Rac, and PAK Signaling in Chemokine-induced Macrophage Migration

Function of p73, not of p53, is inhibited by the physical interaction with RACK1 and its inhibitory effect is counteracted by pRB

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