Rap1A-Deficient T and B Cells Show Impaired Integrin-Mediated Cell Adhesion

Duchniewicz, Marlena; Żemojtel, Tomasz; Kolanczyk, Mateusz; Großmann, S.; Scheele, Jürgen; Zwartkruis, Fried

doi:10.1128/mcb.26.2.643-653.2006

Cited by 104 publications

(94 citation statements)

References 34 publications

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“…MZ B cells are particularly sensitive to deletions of certain GTPases, GAPs (GTPase-activating proteins), and GEFs that promote integrin activation, cell adhesion, and cell migration. For example, deficiencies in Rap1A, Rap1B, DOCK2, or the RhoGEF Lsc result in the loss of B-cell chemotactic responses and in a marked reduction in MZ B cells (7)(8)(9)(10)(11). These findings are consistent with the requisite roles of LFA-1 and VLA-4 integrins, which are highly expressed on MZ B cells compared with follicular B cells (12,13).…”

supporting

confidence: 78%

SHEP1 partners with CasL to promote marginal zone B-cell maturation

Browne¹,

Hoefer²,

Chintalapati³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The marginal zone is a cellular niche bordering the marginal sinus of the spleen that contains specialized B-cell and macrophage subsets poised to capture bloodborne antigens. Marginal zone B cells are retained in this niche by integrin-mediated signaling induced by G protein-coupled receptors (GPCRs) and, likely, the B-cell receptor (BCR). Sphingosine-1-phosphate (S1P) signaling via the S1P family of GPCRs is known to be essential for B-cell localization in the marginal zone, but little is known about the downstream signaling events involved. Here, we demonstrate that the adaptor protein SHEP1 is required for marginal zone B-cell maturation. SHEP1 functions in concert with the scaffolding protein CasL, because we show that SHEP1 and CasL are constitutively associated in B cells. SHEP1 association is required for the BCR or S1P receptor(s) to induce the conversion of CasL into its serine/threonine hyperphosphorylated form, which is important for lymphocyte adhesion and motility. Thus, SHEP1 orchestrates marginal zone B-cell movement and retention as a key downstream effector of the BCR and S1P receptors.Cas-Hef1-associated signal transducer | Sh2d3c | migration | sphingosine-1-phosphate | signaling A dhesion and migration are required for B-cell development, differentiation, and function. B cells traffic to follicular regions in the secondary lymphoid tissues in response to chemokines produced by the follicular stroma (1). In the spleen, the marginal zone (MZ) surrounding the white pulp contains a subset of B cells that are poised to respond to antigens delivered via the blood sinuses. MZ B cells are retained in this niche by integrin signaling induced by "outside-in" signaling via G protein-coupled receptors (GPCRs) and, likely, the B-cell receptor (BCR) (2).The lipid mediator, sphingosine-1-phosphate (S1P), has been shown to be a prominent factor in guiding B cells to the MZ niche (3, 4). Similar to chemokine receptors, such as CXCR4 and CXCR5, S1P receptors act in B cells by coupling to heterotrimeric G proteins and mobilizing calcium (5). S1P has also been shown to induce proximal phosphorylation of focal adhesion kinase and paxillin in fibroblasts, and promote the phosphorylation of downstream adaptors and activation of Ras family GTPases to affect adhesion and migration (6). MZ B cells are particularly sensitive to deletions of certain GTPases, GAPs (GTPase-activating proteins), and GEFs that promote integrin activation, cell adhesion, and cell migration. For example, deficiencies in Rap1A, Rap1B, DOCK2, or the RhoGEF Lsc result in the loss of B-cell chemotactic responses and in a marked reduction in MZ B cells (7-11). These findings are consistent with the requisite roles of LFA-1 and VLA-4 integrins, which are highly expressed on MZ B cells compared with follicular B cells (12, 13). BCR and CXCR4 signaling have also been shown to induce the tyrosine phosphorylation of the scaffolding protein CasL/HEF1 (14, 15). Tyrosine phosphorylation of CasL is required for its interaction with the adaptor CrkL, allowi...

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supporting

confidence: 78%

SHEP1 partners with CasL to promote marginal zone B-cell maturation

Browne¹,

Hoefer²,

Chintalapati³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…36,37 Surviving Rap1A-null mice develop normally, with no gross abnormalities. 37,38 However, upon backcrossing for 6 generations into a C57BL/6J mouse strain, the Mendelian inheritance ratio of Rap1A -/-pups from heterozygous crosses was found to be very slightly reduced (from occur. The remaining Rap1 signal in the 1A knockdown lane likely represents the more abundant Rap1B isoform, confirming previous observations that Rap1B is the major isoform in ECs.…”

Section: Resultsmentioning

confidence: 99%

Isoform-specific differences between Rap1A and Rap1B GTPases in the formation of endothelial cell junctions

Wittchen¹,

Aghajanian²,

Burridge³

2011

Small GTPases

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“…However, recent data suggest that chemoattractant-induced Rap1 signalling at the leading edge is critical for lymphocyte polarity and migration [166,167]. Evidence of a role for mammalian Rap1 in cell migration and polarity includes the observations that lymphocytes expressing a constitutively active Rap1 mutant undergo spontaneous polarization and display increased cell migration, in addition to enhanced adhesion [168] and that rap −/− T-cells present polarization defects [169]. The Rap1-mediated control of cell motility and polarity most likely involves its regulation of adhesion as well as the actin cytoskeleton.…”

Section: Regulation Of Actin-myosin Assemblymentioning

confidence: 99%

Big roles for small GTPases in the control of directed cell movement

Charest

Firtel

2006

Biochemical Journal

179

156

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Small GTPases are involved in the control of diverse cellular behaviours, including cellular growth, differentiation and motility. In addition, recent studies have revealed new roles for small GTPases in the regulation of eukaryotic chemotaxis. Efficient chemotaxis results from co-ordinated chemoattractant gradient sensing, cell polarization and cellular motility, and accumulating data suggest that small GTPase signalling plays a central role in each of these processes as well as in signal relay. The present review summarizes these recent findings, which shed light on the molecular mechanisms by which small GTPases control directed cell migration.

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Rap1A-Deficient T and B Cells Show Impaired Integrin-Mediated Cell Adhesion

Cited by 104 publications

References 34 publications

SHEP1 partners with CasL to promote marginal zone B-cell maturation

SHEP1 partners with CasL to promote marginal zone B-cell maturation

Isoform-specific differences between Rap1A and Rap1B GTPases in the formation of endothelial cell junctions

Big roles for small GTPases in the control of directed cell movement

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