RasGRP, a Ras Guanyl Nucleotide- Releasing Protein with Calcium- and Diacylglycerol-Binding Motifs

Ebinu, Julius O.; Bottorff, Drell A.; Chan, Edmond Y W; Stang, Stacey L.; Dunn, Robert; Stone, James C.

doi:10.1126/science.280.5366.1082

Cited by 617 publications

(550 citation statements)

References 24 publications

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“…The identities of the Ser316 kinase and Ser325 phosphatase acting downstream of PKC have yet to be identified but these studies have ruled out PKA and mitogen-activated protein kinases in this process. In addition to the phorbol ester-binding PKC isoenzymes, PMA has been reported to bind other receptors such as the chimaerins (Caloca et al, 1999), Ras guanyl-releasing protein (ElShemerly et al, 1997;Ebinu et al, 1998) and protein kinase Ds (Van Lint et al, 2002). Importantly, this study and previous studies (Legg et al, 2002) have demonstrated that the effects of PMA treatment on CD44 Ser316 phosphorylation and Ser325 dephosphorylation are mediated via activation of PKC as the PKC inhibitors Ro-31 and Bis-I are effective in blocking these phosphorylation/dephosphorylation events.…”

Section: Discussionmentioning

confidence: 99%

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

2006

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Cancer progression is associated with enhanced directional cell migration, both of the tumour cells invading into the stroma and stromal cells infiltrating the tumour site. In cell-based assays to study directional cell migration, phorbol esters are frequently used as a chemotactic agent. However, the molecular mechanism by which these activators of protein kinase C (PKC) result in the establishment of a polarized migratory phenotype is not known. Here we show that CD44 expression is essential for chemotaxis towards a phorbol ester gradient. In an investigation of CD44 phosphorylation kinetics in resting and stimulated cells, Ser316 was identified as a novel site of phosphorylation following activation of PKC. PKC does not phosphorylate Ser316 directly, but rather mediates the activation of downstream Ser316 kinase(s). In transfection studies, a phosphorylation-deficient Ser316 mutant was shown to act in a dominant-negative fashion to impair chemotaxis mediated by endogenous CD44 in response to a phorbol ester gradient. Importantly, this mutation had no effect on random cell motility or the ability of cells to migrate directionally towards a cocktail of chemoattractants. These studies demonstrate that CD44 functions to provide directional cues to migrating cells without affecting the motility apparatus.

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Section: Discussionmentioning

confidence: 99%

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

2006

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“…First, the recent discovery of cAMPregulated Rap1GEFs (DeRooij et al, 1998;Kawasaki et al, 1998) establishes the precedent for the existence of cAMP-regulated RasGEFs, although to our knowledge these have not yet been described. It is intriguing, however, that novel calcium-activated RasGEFs have been identi®ed (Ebinue et al, 1998;Farnsworth et al, 1995). Second, the e ects of cAMP on Ras activity could be mediated through e ects on GAP activity.…”

Section: Discussionmentioning

confidence: 99%

Cyclic AMP activates Ras

et al. 2000

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In addition to protein kinase A (PKA), cAMP regulates the activity of cAMP-gated channels and Rap1-speci®c guanine nucleotide exchange factors. We tested the hypothesis that the targets of cAMP might also include regulators of the Ras protooncogene. In rat thyroid cells, thyrotropin (TSH) stimulates proliferation through a cAMP-mediated pathway that requires Ras activity. Interference with Ras impairs DNA synthesis stimulated by TSH as well as cAMP elevating agents and analogs, demonstrating that the requirement for Ras lies downstream of cAMP. Although cAMP stimulates proliferation, microinjection of the puri®ed PKA catalytic subunit failed to do so, suggesting that factors in addition to PKA are required for cAMP-stimulated cell cycle progression. When added to thyroid cells expressing human Ha-Ras, TSH rapidly and markedly increased the proportion of GTP-bound Ras. Ras activity was increased within 1 min of TSH addition, maximal at 5 ± 15 min, and declined to basal levels 30 ± 60 min after hormone treatment. Cyclic AMP elevating agents elicited similar e ects on Ras, indicating that TSH activates Ras through a cAMP-mediated pathway. Although cAMP-mediated, Ras activation by TSH and cAMP was independent of PKA activity. Moreover, cAMP-stimulated Ras activation was not impaired by tyrosine kinase inhibitors. These results indicate that cAMP activates targets in addition to PKA in thyroid cells, and that these targets may include regulators of Ras. The ability of cAMP elevating agents to activate Ras in addition to PKA may explain the inability of the PKA catalytic subunit to stimulate DNA synthesis in thyroid cells. Oncogene (2000) 19, 3609 ± 3615.

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“…Major RasGEFs in T cells are Sos (son of sevenless) and RasGRP1 (Ras guanine nucleotide releasing protein 1) [19,20]. RasGRP1 has a DAG-binding C1 domain and a pair of EF hand motifs that bind to Ca 2+ directly [21]. RasGRP1 localizes in the cytoplasm of resting T cells and translocates to the Golgi apparatus in response to weak stimulation, such as with soluble anti-CD3 antibodies or with low-affinity peptides that induce positive selection of thymocytes [22,••23].…”

Section: Integration and Crosstalk Between Ca 2+ And Other Signallingmentioning

confidence: 99%

Calcium signaling in lymphocytes

Oh‐hora¹,

Rao²

2008

Current Opinion in Immunology

353

282

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In cells of the immune system, calcium signals are essential for diverse cellular functions including differentiation, effector function and gene transcription. After engagement of immunoreceptors such as T-cell and B-cell antigen receptors and the Fc receptors on mast cells and NK cells, the intracellular concentration of calcium ions is increased through the sequential operation of two interdependent processes: depletion of endoplasmic reticulum Ca 2+ stores as a result of binding of inositol trisphosphate (IP 3 ) to IP 3 receptors, followed by "store-operated" Ca 2+ entry through plasma membrane Ca 2+ channels. In lymphocytes, mast cells and other immune cell types, store-operated Ca 2+ entry through specialised Ca 2+ release-activated calcium (CRAC) channels constitutes the major pathway of intracellular Ca 2+ increase. A recent breakthrough in our understanding of CRAC channel function is the identification of STIM and ORAI, two essential regulators of CRAC channel function. This review focuses on the signaling pathways upstream and downstream of Ca 2+ influx (the STIM/ ORAI and calcineurin/ NFAT pathways respectively).

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RasGRP, a Ras Guanyl Nucleotide- Releasing Protein with Calcium- and Diacylglycerol-Binding Motifs

Cited by 617 publications

References 24 publications

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

Cyclic AMP activates Ras

Calcium signaling in lymphocytes

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