Myosin IIA is involved in the endocytosis of CXCR4 induced by SDF-1α

Rey, Manuel; Valenzuela-Fernández, Agustı́n; Urzainqui, Ana; Yáñez-Mó, Marı́a; Pérez‐Martínez, Manuel; Penela, Petronila; Mayor, Federico; Sánchez-Madrid, Francisco

doi:10.1242/jcs.03415

Cited by 60 publications

(40 citation statements)

References 55 publications

(55 reference statements)

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“…Therefore, syntenin-1 binding might compete with MBS, shifting the balance towards Racinduced actin polymerization, rather than Rho-mediated contraction. Myosin function in lymphocytes is not restricted to regulation of cell contractility during migration, but also regulates immune synapse maturation (Ilani et al, 2009), cytotoxicity (Andzelm et al, 2007) and chemokine receptor internalization (Rey et al, 2007). MLC phosphorylation is detected at the IS (Ilani et al, 2009) and at the leading edge of migrating polarized lymphocytes (Vicente-Manzanares et al, 2002), both sites of active Rac-induced actin polymerization.…”

Section: Discussionmentioning

confidence: 99%

Association of syntenin-1 with M-RIP polarizes Rac-1 activation during chemotaxis and immune interactions

Sala-Valdés

Gordon-Alonso

Tejera

et al. 2012

Journal of Cell Science

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SummaryIn this study, we describe that the PDZ protein syntenin-1 is a crucial element for the generation of signaling asymmetry during the cellular response to polarized extracellular cues. We analyze the role of syntenin-1 in the control of asymmetry in two independent models of T cell polarization -the migratory response to chemoattractants and the establishment of cognate interactions between T cells and antigenpresenting cells (APCs). A combination of mutant, biochemical and siRNA approaches demonstrate that syntenin-1 is vital for the generation of polarized actin structures such as the leading edge and the contact zone with APCs. We found that the mechanism by which syntenin-1 controls actin polymerization relies on its mandatory role for activation of the small GTPase Rac. Syntenin-1 controls Rac through a specific association with the myosin phosphatase Rho interacting protein (M-RIP), which occurs in response to phosphorylation of syntenin-1 by Src at Tyr4. Our data indicate the key role of syntenin-1 in the generation of functional asymmetry in T cells and provide a novel mechanistic link between receptor activation and actin polymerization and accumulation in response to extracellular stimulation.

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Section: Discussionmentioning

confidence: 99%

Association of syntenin-1 with M-RIP polarizes Rac-1 activation during chemotaxis and immune interactions

Sala-Valdés

Gordon-Alonso

Tejera

et al. 2012

Journal of Cell Science

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“…GRKs phosphorylate Ser/Thr residues of intracellular loops and/or the C-tail of the agonist-activated receptor, a process that enhances the affinity of the receptor for the arrestins. The nonvisual β-arrestin1 and -2 are reported to interact with intracellular domains of CXCR4 and to regulate receptor desensitization and internalization (8)(9)(10)(11). Seven GRKs are known, and among them, the 4 widely expressed members (GRK2, -3, -5, and -6) are supposed to regulate most GPCRs with overlapping receptor specificities (12,13).…”

Section: Introductionmentioning

confidence: 99%

Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling

Balabanian¹,

Levoye²,

Klemm³

et al. 2008

J. Clin. Invest.

105

133

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Leukocytes from individuals with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency, and bearing a wild-type CXCR4 ORF (WHIM WT ) display impaired CXCR4 internalization and desensitization upon exposure to CXCL12. The resulting enhanced CXCR4-dependent responses, including chemotaxis, probably impair leukocyte trafficking and account for the immunohematologic clinical manifestations of WHIM syndrome. We provided here evidence that GPCR kinase-3 (GRK3) specifically regulates CXCL12-promoted internalization and desensitization of CXCR4. GRK3-silenced control cells displayed altered CXCR4 attenuation and enhanced chemotaxis, as did WHIM WT cells. These findings identified GRK3 as a negative regulator of CXCL12-induced chemotaxis and as a candidate responsible for CXCR4 dysfunction in WHIM WT leukocytes. Consistent with this, we showed that GRK3 overexpression in both leukocytes and skin fibroblasts from 2 unrelated WHIM WT patients restored CXCL12-induced internalization and desensitization of CXCR4 and normalized chemotaxis. Moreover, we found in cells derived from one patient a profound and selective decrease in GRK3 products that probably resulted from defective mRNA synthesis. Taken together, these results have revealed a pivotal role for GRK3 in regulating CXCR4 attenuation and have provided a mechanistic link between the GRK3 pathway and the CXCR4-related WHIM WT disorder.

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“…Internalization of CXCR4 after SDF-1 treatment involves interaction with the proteins ferritin (19), 73-kDa heat shock cognate protein (Hsc73) (20), plectin (10) and Myosin IIA (21). A recent study found several proteins, including ferritin (19) and Hsc73 (20), in combination with CXCR4 after internalization of CXCR4.…”

Section: Introductionmentioning

confidence: 99%

“…Plectin is required for CXCR4 internalization, is found in intracellular vesicles with CXCR4 and is required for ERK1/2 signaling (10). Myosin IIA is required for SDF-1-induced endocytosis of CXCR4 (21).…”

Section: Introductionmentioning

confidence: 99%

CXCR4 nuclear localization follows binding of its ligand SDF-1 and occurs in metastatic but not primary renal cell carcinoma

Wang

Wang²,

Yang³

et al. 2009

Oncol Rep

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Abstract. Renal cell carcinoma (RCC) shows organ-specific metastasis. This may be attributed to the fact that the CXCR4 G protein coupled receptor on RCC cells mediates chemoattraction toward stromal-derived factor (SDF)-1 secreted by target organs. SDF-1 binding to CXCR4 initiates many internal signaling cascades as well as internalization of the receptor complex. Here we show that SDF-1 binding localized CXCR4 to the nucleus in A-498 renal carcinoma cells over a 24 h period. CXCR4 nuclear localization in A-498 cells associated with increased Matrigel matrix invasion, a metastatic trait. Comparing histological sections of primary and metastatic human RCC, we found that CXCR4 localized to the nucleus only in metastatic RCC lesions. In conclusion, SDF-1 binding of CXCR4 not only induces immediate signaling via signaling cascades, but also a slower response via nuclear localization of the receptor complex. CXCR4 nuclear localization may be responsible for certain metastatic changes in cancer cells and can be used to distinguish metastatic RCC cells. These findings may be applied to the search for ways to inhibit RCC, as well as to many other questions that involve CXCR4 such as normal hematopoiesis, tissue regeneration, stem cell research and HIV infection.

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Myosin IIA is involved in the endocytosis of CXCR4 induced by SDF-1α

Cited by 60 publications

References 55 publications

Association of syntenin-1 with M-RIP polarizes Rac-1 activation during chemotaxis and immune interactions

Association of syntenin-1 with M-RIP polarizes Rac-1 activation during chemotaxis and immune interactions

Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling

CXCR4 nuclear localization follows binding of its ligand SDF-1 and occurs in metastatic but not primary renal cell carcinoma

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