DEF6, a Novel Substrate for the Tec Kinase ITK, Contains a Glutamine-rich Aggregation-prone Region and Forms Cytoplasmic Granules that Co-localize with P-bodies

Hey, Fiona; Czyzewicz, Nathan; Jones, Peter; Sablitzky, Fred

doi:10.1074/jbc.m112.346767

Cited by 27 publications

(33 citation statements)

References 53 publications

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“…This stretch has a pI of 4.8 and is rich in glutamine and glutamic acid, which together account for 41% of the 81 aa. Glutamine-rich regions were described as modules involved in multimerization of proteins even if present in coiled-coil regions (58), and the only protein closely related to SWAP-70, DEF6, also harbors a Gln/Glu-rich (31%) stretch suggested to be involved in its multimerization, which, however, is functionally different and not related to F-actin dynamics (59).…”

Section: Discussionmentioning

confidence: 99%

The Switch-associated Protein 70 (SWAP-70) Bundles Actin Filaments and Contributes to the Regulation of F-actin Dynamics

Chacón‐Martínez

Kiessling

Winterhoff

et al. 2013

Journal of Biological Chemistry

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Background: Precise spatiotemporal rearrangement of the actin cytoskeleton is essential for cell migration and adhesion. Results: SWAP-70 bundles actin filaments and interacts with cofilin in vitro and in murine mast cells. Conclusion: SWAP-70 is a parallel and anti-parallel bundling protein that participates in the organization of F-actin networks. Significance: Identification and characterization of a regulator of F-actin dynamics improve our understanding on the spatiotemporal control of cytoskeletal processes.

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Section: Discussionmentioning

confidence: 99%

The Switch-associated Protein 70 (SWAP-70) Bundles Actin Filaments and Contributes to the Regulation of F-actin Dynamics

Chacón‐Martínez

Kiessling

Winterhoff

et al. 2013

Journal of Biological Chemistry

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“…Indeed, SWAP-70 and DEF6 can be found in cytoplasmic and nuclear compartments and can also be recruited to the plasma membrane in a stimulation-dependent manner [14–17]. Recent studies have furthermore shown that Def6 contains a glutamine-rich coiled-coil region within its C-terminal region that enables it to aggregate and localize to P-bodies upon cellular stress [18]. …”

Section: The Swef Proteins: General Characteristicsmentioning

confidence: 99%

“…Indeed the absence of DEF6 results in a number of abnormalities in T H cells that include aberrancies in the ability of the TCR to properly gauge the strength of engagement, likely due to improper cytoskeletal reorganization and immunological synapse formation, and defective T H 1 and T H 2 responses that have been deemed secondary to impaired NFAT activation [22, 23]. Additional regulatory events, such as Itk-mediated phosphorylation, have also been recently shown to contribute to the regulation of DEF6 localization and activity [18, 24]. …”

Section: Role Of the Swef Proteins In T Cellsmentioning

confidence: 99%

Regulation of systemic autoimmunity and CD11c + Tbet + B cells by SWEF proteins

Manni

Ricker

Pernis

2017

Cellular Immunology

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Recent studies have revealed the existence of a T-bet dependent subset of B cells, which expresses unique phenotypic and functional characteristics including high levels of CD11c and CD11b. In the murine system this B cell subset has been termed Age/autoimmune-associated B cells (ABCs) since it expands with age in non-autoimmune mice and it prematurely accumulates in autoimmune-prone strains. The molecular mechanisms that promote the expansion and function of ABCs are largely unknown. This review will focus on the SWEF proteins, a small family of Rho GEFs comprised of SWAP-70 and its homolog DEF6, a newly identified risk variant for human SLE. We will first provide an overview of the SWEF proteins and then discuss the complex array of biological processes that they control and the autoimmune phenotypes that spontaneously develop in their absence, highlighting the emerging involvement of these proteins in regulating ABCs. A better understanding of the pathways controlled by the SWEF proteins could help provide new insights into the mechanisms responsible for the expansion of ABCs in autoimmunity and potentially guide the design of novel therapeutic approaches.

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“…12 A number of specific tyrosines targeted by Itk have been identified, including Y783 of PLCγ1, Y180 of Itk, Y173 of SLP-76 and, recently, Y210 as well as Y222 of DEF6. 13–17 Among these Itk-mediated phosphorylation on Y783 of PLCγ1 is the best studied and most important in the context of T cell signaling. Phosphorylation on PLCγ1 Y783 activates the lipase activity of PLCγ1, which generates two essential secondary messengers, diacylglycerol and inositol trisphosphate, by hydrolyzing phosphatidylinositol 4,5-bisphosphate.…”

Section: Introductionmentioning

confidence: 99%

Substrate Recognition of PLCγ1 via a Specific Docking Surface on Itk

Xie

Joseph

Fulton

et al. 2013

Journal of Molecular Biology

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Itk (interleukin-2 inducible T cell kinase) is a non-receptor protein tyrosine kinase expressed primarily in T cells. Itk catalyzes phosphorylation on tyrosine residues within a number of its natural substrates, including the well-characterized Y783 of PLCγ1. However, the molecular mechanisms Itk exploits to recognize its substrates are not completely understood. We have previously identified a specific docking interaction between the kinase domain of Itk and the C-terminal Src homology 2 (SH2C) domain of PLCγ1 that promotes substrate specificity for this enzyme/substrate pair. In the current study, we identify and map the interaction surface on the Itk kinase domain as an acidic patch centered on the G helix. Mutation of the residues on and adjacent to the G helix within the Itk kinase domain impairs the catalytic efficacy of PLCγ1 substrate phosphorylation by specifically altering the protein–protein interaction interface and not the inherent catalytic activity of Itk. NMR titration experiments using a Btk (Bruton’s tyrosine kinase) kinase domain as a surrogate for the Itk kinase domain provide further support for an Itk/PLCγ1 SH2C interaction surrounding the G helix of the kinase domain. The work presented here provides structural insight into how the Itk kinase uses the G helix to single out Y783 of PLCγ1 for specific phosphorylation. Comparing these results to other well-characterized kinase/substrate systems suggests that the G helix is a general structural feature used by kinases for substrate recognition during signaling. Receptor stimulation triggers intracellular phosphorylation cascades that are controlled by the action of protein kinases. The exquisite fidelity of protein kinases in targeting a specific substrate arises from protein–protein interactions remote from the kinase active site. A focused study of the Itk (interleukin-2 inducible T cell kinase)/PLCγ1 kinase/substrate pair in the T cell signaling pathway reveals that the G helix in the large lobe of the Itk kinase domain serves as a substrate handle, directly mediating interaction with PLCγ1 C-terminal Src homology 2 domain to ensure proper substrate selection and site selective phosphorylation during signaling.

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DEF6, a Novel Substrate for the Tec Kinase ITK, Contains a Glutamine-rich Aggregation-prone Region and Forms Cytoplasmic Granules that Co-localize with P-bodies

Cited by 27 publications

References 53 publications

The Switch-associated Protein 70 (SWAP-70) Bundles Actin Filaments and Contributes to the Regulation of F-actin Dynamics

The Switch-associated Protein 70 (SWAP-70) Bundles Actin Filaments and Contributes to the Regulation of F-actin Dynamics

Regulation of systemic autoimmunity and CD11c + Tbet + B cells by SWEF proteins

Substrate Recognition of PLCγ1 via a Specific Docking Surface on Itk

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