The importance of Src homology 2 domain-containing leukocyte phosphoprotein of 76 kilodaltons sterile-α motif domain in thymic selection and T-cell activation

Shen, Shudan; Lau, Jasmine; Zhu, Minghua; Zou, Jian‐Wei; Fuller, Deirdre M.; Li, Qijing; Zhang, Weiguo

doi:10.1182/blood-2008-09-177832

Cited by 12 publications

(17 citation statements)

References 49 publications

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“…3 C ). This showed that the SAM domain was essential for microcluster formation, to a greater extent than previously observed with the partial SAM domain mutant (49). …”

Section: Resultssupporting

confidence: 51%

“…As well, upon migration to the interior of the cell contact region, the smaller dN57 clusters were observed to coalesce to form larger clusters, an event that we would speculate may involve the subsequent recruitment of other associated proteins such as VAV and NCK, which may also contribute to the formation of higher order complex structures. Although the complete loss of SAM completely prevented cluster formation, the partial deletion of residues 12–78 has been described to partially affect the longevity of cluster formation (49). …”

Section: Discussionmentioning

confidence: 99%

“…Previous work has shown that the partial loss ( i.e. residues 12–78) of the SLP-76 SAM region can impair positive and negative thymic selection (49). …”

Section: Introductionmentioning

confidence: 99%

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SLP-76 Sterile α Motif (SAM) and Individual H5 α Helix Mediate Oligomer Formation for Microclusters and T-cell Activation

Liu

Thaker

Stagg

et al. 2013

Journal of Biological Chemistry

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Background: SLP-76 possesses an N-terminal sterile α motif (SAM) domain of unknown function.Results: SLP-76 SAM and its isolated H5 domain self-associates for microclusters and NFAT transcription.Conclusion: SLP-76 self-associates in response to T-cell receptor (TCR) ligation as mediated by the SAM domain.Significance: SAM-mediated SLP-76 dimerization is crucial to understanding how SLP-76 forms complexes for T-cell activation.

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“…3 C ). This showed that the SAM domain was essential for microcluster formation, to a greater extent than previously observed with the partial SAM domain mutant (49). …”

Section: Resultssupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

SLP-76 Sterile α Motif (SAM) and Individual H5 α Helix Mediate Oligomer Formation for Microclusters and T-cell Activation

Liu

Thaker

Stagg

et al. 2013

Journal of Biological Chemistry

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“…The molecular structure of SLP76 consists of an N-terminal sterile-alpha motif (SAM) (41), an acidic domain containing tyrosine residues subject to phosphorylation, a central prolinerich region, and a C-terminal SH2 domain. Phosphorylation of the tyrosines allows the interaction of SLP76 with the adapter Nck, the Rho-family GEF, VAV, and Itk, all via their SH2 domains (5,8,48,49,51).…”

mentioning

confidence: 99%

Functional Cooperation between the Proteins Nck and ADAP Is Fundamental for Actin Reorganization

Pauker

Reicher

Fried

et al. 2011

Molecular and Cellular Biology

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T cell antigen receptor (TCR) activation triggers profound changes in the actin cytoskeleton. In addition to controlling cellular shape and polarity, this process regulates vital T cell responses, such as T cell adhesion, motility, and proliferation. These depend on the recruitment of the signaling proteins Nck and Wiskott-Aldrich syndrome protein (WASp) to the site of TCR activation and on the functional properties of the adapter proteins linker for activation of T cells (LAT) and SH2-domain-containing leukocyte protein of 76 kDa (SLP76). We now demonstrate that Nck is necessary but insufficient for the recruitment of WASp. We show that two pathways lead to SLP76-dependent actin rearrangement. One requires the SLP76 acidic domain, crucial to association with the Nck SH2 domain, and another requires the SLP76 SH2 domain, essential for interaction with the adhesion-and degranulation-promoting adapter protein ADAP. Functional cooperation between Nck and ADAP mediates SLP76-WASp interactions and actin rearrangement. We also reveal the molecular mechanism linking ADAP to actin reorganization.T cell activation triggers multiple molecular events, including the activation of protein tyrosine kinases (PTKs), formation of multiprotein signaling complexes, and activation of enzymes and transcription factors (25,37,47). Cytoskeletal actin reorganization is also dependent on these events initiated at the T cell-antigen-presenting cell (APC) interface, the immunological synapse (IS). Interference with actin dynamics results in an impaired immune response and can induce T cell anergy (40).We and others (2,4,8,11,12,16) have demonstrated complex molecular events linking T cell antigen receptor (TCR) activation to actin rearrangement. One major pathway, mediated by the activation of multiple PTKs, leads to phosphorylation of the adapter molecules linker for activation of T cells (LAT) and SH2-domain-containing leukocyte protein of 76 kDa (SLP76). Phosphorylation of SLP76 leads to recruitment of the Nck adapter molecule, which is associated with key regulators of the actin cytoskeleton Wiskott-Aldrich syndrome protein (WASp) and WAVE2.The molecular structure of SLP76 consists of an N-terminal sterile-alpha motif (SAM) (41), an acidic domain containing tyrosine residues subject to phosphorylation, a central prolinerich region, and a C-terminal SH2 domain. Phosphorylation of the tyrosines allows the interaction of SLP76 with the adapter Nck, the Rho-family GEF, VAV, and Itk, all via their SH2 domains (5,8,48,49,51). The interactions of SLP76, Nck, and VAV are essential for the activation of WASp and its recruitment to the IS (51). TCR engagement also induces the association of the SLP76 SH2 domain with the adhesion-and degranulation-promoting adapter protein (ADAP) and to the serine-threonine kinase hematopoietic progenitor kinase 1 (HPK-1) (38). In addition to SLP76, ADAP is capable of binding other proteins, and it is recruited to the IS (26, 35). The role of ADAP in integrin function has been explored (10,23,36,46); however, it...

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“…The N-terminal SAM domain is essential for optimal thymic differentiation and cell activation (22, 23). SAM domains are known to interact with themselves or with other SAM domain-containing proteins or non-SAM domain-containing proteins in a homotypic or heterotypic fashion (24).…”

Section: Introductionmentioning

confidence: 99%

Activated Cdc42-associated kinase 1 (ACK1) binds the sterile α motif (SAM) domain of the adaptor SLP-76 and phosphorylates proximal tyrosines

Thaker

Recino

Raab

et al. 2017

Journal of Biological Chemistry

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The adaptor protein Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) plays a crucial role in T cell activation by linking antigen receptor (T cell receptor, TCR) signals to downstream pathways. At its N terminus, SLP-76 has three key tyrosines (Tyr-113, Tyr-128, and Tyr-145, “3Y”) as well as a sterile α motif (SAM) domain whose function is unclear. We showed previously that the SAM domain has two binding regions that mediate dimer and oligomer formation. In this study, we have identified SAM domain-carrying non-receptor tyrosine kinase, activated Cdc42-associated tyrosine kinase 1 (ACK1; also known as Tnk2, tyrosine kinase non-receptor 2) as a novel binding partner of SLP-76. Co-precipitation, laser-scanning confocal microscopy, and in situ proximity analysis confirmed the binding of ACK1 to SLP-76. Further, the interaction was induced in response to the anti-TCR ligation and abrogated by the deletion of SLP-76 SAM domain (ΔSAM) or mutation of Tyr-113, Tyr-128, and Tyr-145 to phenylalanine (3Y3F). ACK1 induced phosphorylation of the SLP-76 N-terminal tyrosines (3Y) dependent on the SAM domain. Further, ACK1 promoted calcium flux and NFAT-AP1 promoter activity and decreased the motility of murine CD4+ primary T cells on ICAM-1-coated plates, an event reversed by a small molecule inhibitor of ACK1 (AIM-100). These findings identify ACK1 as a novel SLP-76-associated protein-tyrosine kinase that modulates early activation events in T cells.

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The importance of Src homology 2 domain-containing leukocyte phosphoprotein of 76 kilodaltons sterile-α motif domain in thymic selection and T-cell activation

Cited by 12 publications

References 49 publications

SLP-76 Sterile α Motif (SAM) and Individual H5 α Helix Mediate Oligomer Formation for Microclusters and T-cell Activation

SLP-76 Sterile α Motif (SAM) and Individual H5 α Helix Mediate Oligomer Formation for Microclusters and T-cell Activation

Functional Cooperation between the Proteins Nck and ADAP Is Fundamental for Actin Reorganization

Activated Cdc42-associated kinase 1 (ACK1) binds the sterile α motif (SAM) domain of the adaptor SLP-76 and phosphorylates proximal tyrosines

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