Cytoskeletal protein 4.1R negatively regulates T-cell activation by inhibiting the phosphorylation of LAT

Kang, Qiaozhen; Yu, Yu; Pei, Xinhong; Hughes, Richard A.; Heck, Susanne; Zhang, Xihui; Guo, Xinhua; Halverson, Gregory R.; Mohandas, Narla; An, Xiuli

doi:10.1182/blood-2008-10-182329

Cited by 39 publications

(49 citation statements)

References 53 publications

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“…For example, we have documented that, in CD4 ϩ T cells, lack of 4.1R results in hyper-phosphorylation of the adapter protein linker of activation of T cells (LAT) and enhanced downstream signal transduction, implying that 4.1R negatively regulates signal transduction in CD4 ϩ cells (38). In contrast, here we show that lack of 4.1G in MEF cells led to impaired phosphorylation of FAK.…”

Section: Discussioncontrasting

confidence: 44%

“…Here we show that, in MEF cells, lack of 4.1G leads to decreased surface expression of ␤1 integrin without affecting overall ␤1 integrin expression. Given the findings that some other protein 4.1 members, such as 4.1N and 4.1R, play an important role in intracellular protein traffic (37,38) and that integrins undergo extensive intracellular trafficking (39,40), it is reasonable to speculate that protein 4.1 family members affect the expression of their binding partners through different mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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Protein 4.1G Regulates Cell Adhesion, Spreading, and Migration of Mouse Embryonic Fibroblasts through the β1 Integrin Pathway

Chen

Wang

et al. 2016

Journal of Biological Chemistry

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Cell adhesion, spreading, and migration are inseparable features of many biological and pathological processes, including normal development, angiogenesis, wound repair, tumor invasion, and metastasis. The process of cell adhesion and the subsequent spreading and migration on the extracellular matrix involves dynamic changes in the cytoskeleton through the action of integrins, which transduce signals from the outside to the inside of the cell and vice versa (1, 2).Integrins are heterodimeric transmembrane cell adhesion molecules comprising ␣ and ␤ subunits (3). As receptors for the extracellular matrix, integrins play important roles in mediating the signals from the extracellular matrix (4). The signals propagated by extracellular matrix-integrin interactions result in the activation of a number of signaling pathways (5). These pathways include protein tyrosine kinases, such as focal adhesion kinase (FAK) 3 (6), and members of the Rho family of small GTP-binding proteins, such as Cdc42, Rac1, and RhoA (7), which play important roles in regulating the organization of the cytoskeleton. Activated FAK and Rho-GTPase regulate cell adhesion, spreading, and migration (8, 9).One important feature of integrins is that they can shift between low-and high-affinity conformations for ligand binding. The shift from a low-to a high-affinity state is termed "integrin activation" (10). Because altered integrin activation is associated with many diseases, such as bleeding disorders, leukocyte adhesion deficiencies, and skin blistering, integrin activation has to be controlled stringently (11). It was originally thought that talin is the only master regulator of integrin activation (12). Later works have shown that the kindlin family of proteins is as important as talin in mediating integrin function (13,14). Both talin and kindlins belong to a family of evolutionarily conserved FERM (four-point-one, ezrin, radixin, moesin) domain-containing proteins (15). They regulate integrin function by binding directly to the cytoplasmic tail of integrin via their FERM domain, which triggers a conformational change in the extracellular ligand-binding domain, increasing its affinity for its ligand (10, 16). These findings suggest that other FERM domain-containing proteins may also associate with integrin and regulate integrin function.Protein 4.1 family members (which includes 4.1R, 4.1B, 4.1G, and 4.1N) are the prototypical members of the FERM domaincontaining superfamily of proteins. We have shown recently that 4.1R binds to ␤1 integrin and modulates the surface expression of ␤1 integrin in keratinocytes (17). A study by McCarty et al. (18) has also documented the association of 4.1B with ␤8 integrin in cultured astrocytes and in the brain. In this study, we identified a novel role of 4.1G in cell adhesion, spreading, and migration of mouse embryonic fibroblasts by modulating the surface expression of ␤1 integrin through a direct association between 4.1G and ␤1 integrin.

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Section: Discussioncontrasting

confidence: 44%

Section: Discussionmentioning

confidence: 99%

Protein 4.1G Regulates Cell Adhesion, Spreading, and Migration of Mouse Embryonic Fibroblasts through the β1 Integrin Pathway

Chen

Wang

et al. 2016

Journal of Biological Chemistry

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“…In erythrocytes, 4.1R associates with six membrane proteins and forms the core of the 4.1R-based macromolecular complex, and 4.1R deficiency in erythrocytes leads to the altered expression of the 4.1R-associated proteins (2). In CD4 ϩ T cells, 4.1R binds to the adaptor protein LAT (linker of activation of T cells) and inhibits the phosphorylation of LAT (9). In stomach epithelia, lack of 4.1R results in altered adherens junction formation due to the decreased expression of ␤-catenin (11).…”

Section: Discussionmentioning

confidence: 99%

“…The 4.1R isoforms are widely expressed in tissues and are located in a variety of subcellular compartments besides the plasma membrane (5). These include the nucleus (6), nuclear matrix (7), centrosome (8), and immunological synapse (9). In particular, it has been shown that 4.1R is expressed in many epithelial tissues (10,11) and epithelial cell lines (12,13).…”

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confidence: 99%

Impaired Intestinal Calcium Absorption in Protein 4.1R-deficient Mice Due to Altered Expression of Plasma Membrane Calcium ATPase 1b (PMCA1b)

Liu

Weng

Chen

et al. 2013

Journal of Biological Chemistry

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Background:The function of protein 4.1R in small intestinal epithelia is unknown. Results: 4.1R deficiency resulted in decreased expression of PMCA1b and impaired small intestinal calcium absorption. Conclusion: Protein 4.1R plays an important role in small intestinal calcium absorption. Significance: Our results identify a novel function for protein 4.1R and offer new insights into the mechanism of calcium absorption.

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“…Other molecules that may mediate inhibitory signaling are the adapter SLAP (Src-like adapter protein) (Myers et al 2006), the tyrosine phosphatase SHP-1 (Lorenz 2009) and 4.1R (Diakowski et al 2006). 4.1R binds LAT directly and is thought to prevent LAT phosphorylation by ZAP-70 (Kang et al 2009). …”

Section: Lat Interactions Also Inhibit Tcr Signal Transductionmentioning

confidence: 99%

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

Balagopalan¹,

Coussens²,

Sherman³

et al. 2010

Cold Spring Harbor Perspectives in Biology

152

184

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The adapter molecule LAT is a nucleating site for multiprotein signaling complexes that are vital for the function and differentiation of T cells. Extensive investigation of LAT in multiple experimental systems has led to an integrated understanding of the formation, composition, regulation, dynamic movement, and function of LAT-nucleated signaling complexes. This review discusses interactions of signaling molecules that bind directly or indirectly to LAT and the role of cooperativity in stabilizing LAT-nucleated signaling complexes. In addition, it focuses on how imaging studies visualize signaling assemblies as signaling clusters and demonstrate their dynamic nature and cellular fate. Finally, this review explores the function of LAT based on the interpretation of mouse models using various LAT mutants.

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Cytoskeletal protein 4.1R negatively regulates T-cell activation by inhibiting the phosphorylation of LAT

Cited by 39 publications

References 53 publications

Protein 4.1G Regulates Cell Adhesion, Spreading, and Migration of Mouse Embryonic Fibroblasts through the β1 Integrin Pathway

Protein 4.1G Regulates Cell Adhesion, Spreading, and Migration of Mouse Embryonic Fibroblasts through the β1 Integrin Pathway

Impaired Intestinal Calcium Absorption in Protein 4.1R-deficient Mice Due to Altered Expression of Plasma Membrane Calcium ATPase 1b (PMCA1b)

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

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