The Rap GTPases Regulate Integrin-mediated Adhesion, Cell Spreading, Actin Polymerization, and Pyk2 Tyrosine Phosphorylation in B Lymphocytes

McLeod, Sarah J.; Shum, Andrew J.; Lee, Rosaline L.; Takei, Fumio; Gold, Michael R.

doi:10.1074/jbc.m313098200

Cited by 130 publications

(148 citation statements)

References 69 publications

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“…Overexpression of SPAR containing a functional GAP domain caused substantial inactivation of cotransfected Rap1 and Rap2 (blots in Fig. 4 A, B, wtSPAR and ⌬PDZ, Fc treatment), as previously shown for other Rap GTPaseactivating proteins (Tsukamoto et al, 1999;Shimonaka et al, 2003;McLeod et al, 2004). Nevertheless, ephrin-A1 Fc stimulation still significantly decreased Rap1 and Rap2 activation in cells expressing wild-type SPAR (Fig.…”

Section: Spar Mediates Rap1 and Rap2 Inactivation Downstream Of Epha4mentioning

confidence: 74%

The EphA4 Receptor Regulates Neuronal Morphology through SPAR-Mediated Inactivation of Rap GTPases

Richter

Murai²,

Bourgin³

et al. 2007

J. Neurosci.

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Section: Spar Mediates Rap1 and Rap2 Inactivation Downstream Of Epha4mentioning

confidence: 74%

The EphA4 Receptor Regulates Neuronal Morphology through SPAR-Mediated Inactivation of Rap GTPases

Richter

Murai²,

Bourgin³

et al. 2007

J. Neurosci.

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“…The environment, including stromal cells, in the BM has been well documented to play a critical role in the successful development of NK cells (67,68). Stromal cells contain at least two key factors that are essential for NK cell maturation, i.e., LT␤R, which interacts with the membrane-bond form of LT (LT␣1␤ 2 ) (67) and the cytokine IL-15 (69).…”

Section: Discussionmentioning

confidence: 99%

Differential and Nonredundant Roles of Phospholipase Cγ2 and Phospholipase Cγ1 in the Terminal Maturation of NK Cells

Regunathan

Chen

Kutlesa

et al. 2006

The Journal of Immunology

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NK cells play a central role in mediating innate immune responses. Activation of NK cells results in cytotoxicity, cytokine, and chemokine secretions. In this study, we show that in mice with targeted deletion of phospholipase Cγ (PLCγ)2, one of the key signal transducers, there are profound effects on the development and terminal maturation of NK cells. Lack of PLCγ2 significantly impaired the ability of lineage-committed NK precursor cells to acquire subset-specific Ly49 receptors and thereby terminal maturation of NK cells. Overexpression of isozyme, PLCγ1, in PLCγ2-deficient NK cells resulted in the successful Ly49 acquisition and terminal maturation of the NK cells; however, it could only partially rescue NKG2D-mediated cytotoxicity with no cytokine production. Furthermore, PLCγ2-deficient NK cells failed to mediate antitumor cytotoxicity and inflammatory cytokine production, displaying a generalized hyporesponsiveness. Our results strongly demonstrate that PLCγ1 and PLCγ2 play nonredundant and obligatory roles in NK cell ontogeny and in its effector functions.

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“…Rap1 has been shown to be a regulator of leukocyte adhesion through its ability to activate adhesion receptors such as ␤2 integrins (22,58), and similarly to Rap1, Rap2 is a regulator of integrin-mediated adhesion of B cells (59). Because NO activates Rap1 and Rap2 in PMNs made adherent by ␤2 integrins, we assessed whether NO production was required for PMN adhesion.…”

Section: Engagement Of ␤2 Integrins On Human Pmnsmentioning

confidence: 99%

Nitric Oxide Produced in Response to Engagement of β2 Integrins on Human Neutrophils Activates the Monomeric GTPases Rap1 and Rap2 and Promotes Adhesion

Jenei

Deevi

Adams

et al. 2006

Journal of Biological Chemistry

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We found that engagement of ␤2 integrins on human neutrophils increased the levels of GTP-bound Rap1 and Rap2. Also, the activation of Rap1 was blocked by PP1, SU6656, LY294002, GF109203X, or BAPTA-AM, which indicates that the downstream signaling events in Rap1 activation involve Src tyrosine kinases, phosphoinositide 3-kinase, protein kinase C, and release of calcium. Surprisingly, the ␤2 integrin-induced activation of Rap2 was not regulated by any of the signaling pathways mentioned above. However, we identified nitric oxide as the signaling molecule involved in ␤2 integrin-induced activation of Rap1 and Rap2. This was illustrated by the fact that engagement of ␤2 integrins increased the production of nitrite, a stable end-product of nitric oxide. Furthermore, pretreatment of neutrophils with N -monomethyl-L-arginine, or 1400W, which are inhibitors of inducible nitric-oxide synthase, blocked ␤2 integrin-induced activation of Rap1 and Rap2. Similarly, R p -8pCPT-cGMPS, an inhibitor of cGMP-dependent serine/threonine kinases, also blunted the ␤2 integrin-induced activation of Rap GTPases. Also nitric oxide production and its downstream activation of cGMP-dependent serine/threonine kinases were essential for proper neutrophil adhesion by ␤2 integrins. Thus, we made the novel findings that ␤2 integrin engagement on human neutrophils triggers production of nitric oxide and its downstream signaling is essential for activation of Rap GTPases and neutrophil adhesion.

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The Rap GTPases Regulate Integrin-mediated Adhesion, Cell Spreading, Actin Polymerization, and Pyk2 Tyrosine Phosphorylation in B Lymphocytes

Cited by 130 publications

References 69 publications

The EphA4 Receptor Regulates Neuronal Morphology through SPAR-Mediated Inactivation of Rap GTPases

The EphA4 Receptor Regulates Neuronal Morphology through SPAR-Mediated Inactivation of Rap GTPases

Differential and Nonredundant Roles of Phospholipase Cγ2 and Phospholipase Cγ1 in the Terminal Maturation of NK Cells

Nitric Oxide Produced in Response to Engagement of β2 Integrins on Human Neutrophils Activates the Monomeric GTPases Rap1 and Rap2 and Promotes Adhesion

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