Differential Requirements for DOCK2 and Phosphoinositide-3-Kinase γ during T and B Lymphocyte Homing

Nombela‐Arrieta, César; Lacalle, Rosa Ana; Montoya, Marı́a C.; Kunisaki, Yuya; Megı́as, Diego; Marqués, Miriam; Carrera, Ana C.; Mañes, Santos; Fukui, Yoshihiro; Martı́nez-A, Carlos; Stein, Jens V

doi:10.1016/j.immuni.2004.07.012

Cited by 211 publications

(276 citation statements)

References 51 publications

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“…In support of the view that CRK proteins do not signal through DOCK2 in this system, the phenotypes of DOCK2 and CRK/CRKL-deficient T cells are very different. In Dock2 -/-T cells, chemokine-induced RAC1 activation and actin polymerization are almost entirely abolished (37), while adhesion and transendothelial migration are fairly normal (38,39). In contrast, we found that CRK/CRKL-deficient T cells exhibit clear defects in adhesion and diapedesis, with more modest defects in migration.…”

Section: Discussionmentioning

confidence: 93%

CRK proteins selectively regulate T cell migration into inflamed tissues

Huang¹,

Clarke²,

Karimi³

et al. 2015

J. Clin. Invest.

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R e s e a R c h a R t i c l e1 0 2 0 jci.org Volume 125 Number 3 March 2015 therapeutic implications, since they can carry out graftversus-leukemia (GVL) responses with minimal GVHD. Results Generation and characterization of T cell-specific CRK T cells (data not shown).Western blotting of purified CD4 + T cells from Dko and WT mice revealed that levels of CRKI, CRKII, and CRKL in the mutant T cells were reduced by at least 95% ( Figure 1A and data not shown), and flow cytometric analysis confirmed loss of CRK protein expression (Figure 1, B and C).CRK/CRKL Dko mice were born at Mendelian ratios, and spleen, thymus, and lymph nodes exhibited normal cellularity (data not shown). Thymocyte populations were similar in WT and Dko mice, indicating that T cell development proceeded normally ( Figure 1D). Peripheral lymphoid organs showed no differences in proportions of CD4 + and CD8 + T cells, naive (CD62L hi CD44 lo ), memory (CD62L lo CD44 hi ), or activated (CD69 hi ) T cell subsets (Figure 1, D and E, and data not shown). Thus, these mice represented a suitable source of mature CRK/CRKL Dko T cells for functional studies. CRK/CRKL-deficient T cells show defects in adhesion and polarization.Since CRK proteins control adhesion in non-hematopoietic cells (4), we first asked whether integrin-dependent adhesion is defective in CRK/CRKL Dko T cells. On plates coated with ICAM-1, the ligand for the β 2 integrin LFA-1, WT preactivated CD4 + T cells showed about 10% basal binding, which was increased 2-to 5-fold after stimulation with the chemokines CXCL12 or CCL21, or anti-CD3 (Figure 2A). CRK/CRKL Dko T cells showed a significant reduction in adhesion to ICAM-1 under both basal and stimulated conditions. Indeed, chemokine stimulation induced almost no increased adhesion in these cells. Treatment with PMA bypassed the defect. This is most likely because the defect in CRK/CRKL Dko cells lies upstream of PKC signaling in the pathway leading to integrin activation, though PKC activation could also drive a parallel

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Section: Discussionmentioning

confidence: 93%

CRK proteins selectively regulate T cell migration into inflamed tissues

Huang¹,

Clarke²,

Karimi³

et al. 2015

J. Clin. Invest.

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“…Given the general crucial role of PKB in cell motility [23], it is not surprising to observe a key contribution of PKB in lymphocyte chemotactic migration. Indeed, activation of PKB is induced by S1P (ligand for S1P1) [34], CCL19/CCL21 (ligands for CCR7) [34], CXCL13 (ligand for CXCR5) [34] and CXCL12 (ligand for CXCR4) [35], most probably downstream of PI3 K [34]. Interestingly, PKB dependent phosphorylation of S1P1 is required for S1P1 mediated chemotaxis [36].…”

Section: Immune Cell Intrinsic Role Of Pkb In Motility Activation Dmentioning

confidence: 99%

PKB/Akt-dependent regulation of inflammation in cancer

Tang

Wang

Hemmings

et al. 2018

Seminars in Cancer Biology

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A B S T R A C TChronic inflammation is a major cause of human cancer. Clinical cancer therapies against inflammatory risk factors are strategically determined. To rationally guide a novel drug development, an improved mechanistic understanding on the pathological connection between inflammation and carcinogenesis is essential. PI3K-PKB signaling axis has been extensively studied and shown to be one of the key oncogenic drivers in most types of cancer. Pharmacological inhibition of the components along this signaling axis is of great interest for developing novel therapies. Interestingly, emerging studies have shown a close association between PKB activation and inflammatory activity in the vicinity of the tumor, and either blockade of PKB or attenuation of para-tumoral inflammation reveals a mutual-interactive pattern through pathway crosstalk. In this review, we intend to discuss recent advances of PKB-regulated chronic inflammation and its potential impacts on tumor development.

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“…In normal lymphocytes, optimal polarization and migration in response to CCL19, CCL21 or CXCL12 is dependent on the expression of DOCK2, a Rac GTPase exchange factor, and PI3K. Whereas in T cells PI3K-dependent migration is mainly mediated by PI3Kγ, in B cells class IA PI3K is required for their efficient chemotaxis and homing to LNs (7,8).…”

Section: Ccl19 and Ccl21 Increase B-cll Cells Survivalmentioning

confidence: 99%

“…Class I PI3Ks are heterodimeric molecules composed by a regulatory and a catalytic subunit that generate phosphatidylinositol-3,4,5-triphosphate (PIP3), which have a key role in cell migration (6). Class I PI3Ks are further subdivided into class IA and class IB isoforms, which are involved in the chemotaxis and homing of B and T lymphocytes, respectively (7,8).…”

Section: Introductionmentioning

confidence: 99%

Analysis of migratory and prosurvival pathways induced by the homeostatic chemokines CCL19 and CCL21 in B-cell chronic lymphocytic leukemia

Cuesta-Mateos

López-Giral

Alfonso-Pérez

et al. 2010

Experimental Hematology

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The CCR7 chemokine receptor has been reported to promote the localization of chronic lymphocytic leukemia (CLL) cells into lymph nodes (LNs) where they may gain survival signals, but the mechanisms mediating these effects are largely unknown. We investigated the role of different signaling pathways in the migratory and prosurvival effects exerted by the chemokines CCL19 and CCL21, the CCR7 ligands, in CLL cells. Their 3

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Differential Requirements for DOCK2 and Phosphoinositide-3-Kinase γ during T and B Lymphocyte Homing

Cited by 211 publications

References 51 publications

CRK proteins selectively regulate T cell migration into inflamed tissues

CRK proteins selectively regulate T cell migration into inflamed tissues

PKB/Akt-dependent regulation of inflammation in cancer

Analysis of migratory and prosurvival pathways induced by the homeostatic chemokines CCL19 and CCL21 in B-cell chronic lymphocytic leukemia

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