Attenuation of T Cell Receptor Signaling by Serine Phosphorylation-mediated Lysine 30 Ubiquitination of SLP-76 Protein

Wang, Xiaohong; Li, Ju Pi; Chiu, Li Li; Lan, Joung Liang; Chen, Der Yuan; Boomer, Jonathan S.; Tan, Tse‐Hua

doi:10.1074/jbc.m112.371062

Cited by 45 publications

(40 citation statements)

References 29 publications

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“…First, the interaction between SLP-76 and ADAP may simply enhance the overall avidity of the interactions that maintain SLP-76 microclusters. Second, in the absence of ADAP, the serinethreonine kinase HPK1 may gain increased access to microclusters, which it may destabilize by promoting the ubiquitylation and degradation of SLP-76 and Gads (di Bartolo et al, 2007;Shui et al, 2007;Patzak et al, 2010;Lasserre et al, 2011;Wang et al, 2012;Coussens et al, 2013). Third, ADAP may contribute to the exclusion or inactivation of the Cbl family E3 ubiquitin ligases, which promote the degradation of LAT, SLP-76, Vav1 and WASP, and attenuate microcluster lifetimes (Krawczyk et al, 2000;Miura-Shimura et al, 2003;Chiang et al, 2004;Barr et al, 2006;Balagopalan et al, 2007Balagopalan et al, , 2011Chiang et al, 2009;Chiang and Hodes, 2011;Reicher et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

ADAP is an upstream regulator that precedes SLP-76 at sites of TCR engagement and stabilizes signaling microclusters

Lewis

Scangarello

Murphy

et al. 2018

Journal of Cell Science

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Antigen recognition by the T cell receptor (TCR) directs the assembly of essential signaling complexes known as SLP-76 (also known as LCP2) microclusters. Here, we show that the interaction of the adhesion and degranulation-promoting adaptor protein (ADAP; also known as FYB1) with SLP-76 enables the formation of persistent microclusters and the stabilization of T cell contacts, promotes integrin-independent adhesion and enables the upregulation of CD69. By analyzing point mutants and using a novel phosphospecific antibody, we show that Y595 is essential for normal ADAP function, that virtually all tyrosine phosphorylation of ADAP is restricted to a Y595-phosphorylated (pY595) pool, and that multivalent interactions between the SLP-76 SH2 domain and its binding sites in ADAP are required to sustain ADAP phosphorylation. Although pY595 ADAP enters SLP-76 microclusters, nonphosphorylated ADAP is enriched in protrusive actin-rich structures. The pre-positioning of ADAP at the contact sites generated by these structures favors the retention of nascent SLP-76 oligomers and their assembly into persistent microclusters. Although ADAP is frequently depicted as an effector of SLP-76, our findings reveal that ADAP acts upstream of SLP-76 to convert labile, Ca 2+-competent microclusters into stable adhesive junctions with enhanced signaling potential.

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Section: Discussionmentioning

confidence: 99%

ADAP is an upstream regulator that precedes SLP-76 at sites of TCR engagement and stabilizes signaling microclusters

Lewis

Scangarello

Murphy

et al. 2018

Journal of Cell Science

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“…This downregulation is due to the inactivation of NF-B, which binds to the Btk promoter and induces transcription of Btk (56). Moreover, it has been reported that 14-3-3 binding can stimulate ubiquitination, resulting in degradation of its partner proteins, such as SLP-76 and Mdmx (57,58). Interestingly, BLNK, also known as SLP-65, which in B cells has a function related to that of SLP-76 in T cells, is also regulated by 14-3-3.…”

Section: Discussionmentioning

confidence: 99%

Dual Phosphorylation of Btk by Akt/Protein Kinase B Provides Docking for 14-3-3ζ, Regulates Shuttling, and Attenuates both Tonic and Induced Signaling in B Cells

Mohammad

Nore

Hussain

et al. 2013

Molecular and Cellular Biology

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“…51 In T cells, SLP-76 is phosphorylated by HPK1, leading to binding of 14-3-3, ubiquitination, and degradation of SLP-76 with subsequent attenuation of TCR signaling. [45][46][47]52 Moreover, HPK1 competes with ADAP for SLP-76 binding in T cells and thereby decreases the amount of active Rap1, an activator of highaffinity LFA-1. 25 In PMNs, SLP-76 is involved in integrin activation, as well as in outside-in signaling and subsequent cell spreading.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic progenitor kinase 1 (HPK1) is required for LFA-1–mediated neutrophil recruitment during the acute inflammatory response

Jakob

Pick

Brechtefeld

et al. 2013

Blood

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Key Points• Hematopoietic progenitor kinase 1 (HPK1) regulates LFA-1 affinity and thereby controls adhesion and postadhesion functions of neutrophils.• Hematopoietic progenitor kinase 1 (HPK1) is critically involved in neutrophil trafficking during acute inflammation.Recruitment of polymorphonuclear neutrophils (PMNs) to sites of acute inflammation critically depends on b 2 integrins (CD11/CD18). Recently, the mammalian actin-binding protein 1 (mAbp1) was identified as an important adaptor protein regulating PMN trafficking downstream of b 2 integrins. Here, we show that mAbp1 constitutively co-immunoprecipitated with hematopoietic progenitor kinase 1 (HPK1) in neutrophillike differentiated HL-60 (dHL-60) cells. HPK1 was enriched at the lamellipodium of polarized dHL-60 cells, where it colocalized with mAbp1 and actin. Functional analysis of PMNs from HPK1-deficient mice showed that HPK1 was critical for CXCL1-induced lymphocyte function-associated antigen 1 (LFA-1)-mediated PMN adhesion to ICAM-1 under flow conditions. Accordingly, CXCL1-mediated induction of high-affinity LFA-1 required HPK1, but macrophage antigen 1 (Mac-1) affinity regulation was independent of HPK1. Intravital microscopy of the mouse cremaster muscle confirmed the defect of CXCL1-induced leukocyte adhesion in HPK1-deficient mice. Furthermore, b 2 integrin-mediated post-adhesion processes-adhesion strengthening, spreading, and directed mechanotactic crawling of PMNs under flow conditions-involved HPK1 in vitro and in vivo. Upon intrascrotal administration of tumor necrosis factor a (TNF-a), PMN adhesion and extravasation were severely compromised in HPK1-deficient mice. In summary, our results indicate that HPK1 is critically involved in LFA-1-mediated PMN trafficking during acute inflammation. (Blood. 2013;121(20):4184-4194)

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Attenuation of T Cell Receptor Signaling by Serine Phosphorylation-mediated Lysine 30 Ubiquitination of SLP-76 Protein

Cited by 45 publications

References 29 publications

ADAP is an upstream regulator that precedes SLP-76 at sites of TCR engagement and stabilizes signaling microclusters

ADAP is an upstream regulator that precedes SLP-76 at sites of TCR engagement and stabilizes signaling microclusters

Dual Phosphorylation of Btk by Akt/Protein Kinase B Provides Docking for 14-3-3ζ, Regulates Shuttling, and Attenuates both Tonic and Induced Signaling in B Cells

Hematopoietic progenitor kinase 1 (HPK1) is required for LFA-1–mediated neutrophil recruitment during the acute inflammatory response

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