Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization

Chung, Jean K.; Nocka, Laura M.; Wang, Qi; Kadlecek, Theresa A.; Weiss, Arthur; Kuriyan, John; Groves, Jay T.

doi:10.1101/284000

Cited by 12 publications

(17 citation statements)

References 52 publications

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“…Interaction with Nef may relieve this negative regulatory influence by displacing the PH domain, in a manner analogous to regulatory SH3 domain displacement associated with Nef-dependent activation of the Src-family kinase, Hck (16,40). Furthermore, membrane PIP3 may also drive Btk dimer formation as part of a unique activation mechanism not shared by Itk (41). In this case, Nef may exploit and enhance this natural mechanism of Btk activation by stabilizing preformed dimers at the membrane.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Nef dimers short-circuit immune receptor signaling by activating Tec-family kinases at the host cell membrane

Li¹,

Aryal

Shu

et al. 2020

Journal of Biological Chemistry

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The HIV-1 virulence factor Nef promotes high-titer viral replication, immune escape, and pathogenicity. Nef interacts with interleukin-2–inducible T-cell kinase (Itk) and Bruton's tyrosine kinase (Btk), two Tec-family kinases expressed in HIV-1 target cells (CD4 T cells and macrophages, respectively). Using a cell-based bimolecular fluorescence complementation assay, here we demonstrate that Nef recruits both Itk and Btk to the cell membrane and induces constitutive kinase activation in transfected 293T cells. Nef homodimerization-defective mutants retained their interaction with both kinases but failed to induce activation, supporting a role for Nef homodimer formation in the activation mechanism. HIV-1 infection up-regulates endogenous Itk activity in SupT1 T cells and donor-derived peripheral blood mononuclear cells. However, HIV-1 strains expressing Nef variants with mutations in the dimerization interface replicated poorly and were significantly attenuated in Itk activation. We conclude that direct activation of Itk and Btk by Nef at the membrane in HIV-infected cells may override normal immune receptor control of Tec-family kinase activity to enhance the viral life cycle.

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Section: Discussionmentioning

confidence: 99%

HIV-1 Nef dimers short-circuit immune receptor signaling by activating Tec-family kinases at the host cell membrane

Li¹,

Aryal

Shu

et al. 2020

Journal of Biological Chemistry

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“…The physical differences between events that increase proximity of MST1/2 kinase domains will affect both the level and lifetime of autophosphorylated MST1/2 and, thus, modulate the downstream response. Trans-autophosphorylation reactions inherently represent a positive feedback switch with the rate of activation dependent on the magnitude of the change in effective concentration (78)(79)(80)(81). Not all activating events will result in the same change in effective concentration; for example, based on linker lengths, homodimerization of MST1/2 will raise effective concentration of MST1/2 higher than complex formation with SAV1 (82).…”

Section: Discussionmentioning

confidence: 99%

Increasing kinase domain proximity promotes MST2 autophosphorylation during Hippo signaling

Tran

Mitra

et al. 2020

Journal of Biological Chemistry

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The Hippo pathway plays an important role in developmental biology, mediating organ size by controlling cell proliferation through the activity of a core kinase cassette. Multiple upstream events activate the pathway, but how each controls this core kinase cassette is not fully understood. Activation of the core kinase cassette begins with phosphorylation of the kinase MST1/2 (also known as STK3/4). Here, using a combination of in vitro biochemistry, and cell-based assays including chemically induced dimerization and single-molecule pull down we revealed that increasing the proximity of adjacent kinase domains, rather than formation of a specific protein assembly, is sufficient to trigger autophosphorylation. We validate this mechanism in cells and demonstrate that multiple events associated with the active pathway, including SARAH-domain mediated homodimerization, membrane recruitment, and complex formation with the effector protein SAV1, each increase the kinase domain proximity and autophosphorylation of MST2. Together, our results reveal that multiple and distinct upstream signals each utilize the same common molecular mechanism to stimulate MST2 autophosphorylation. This mechanism is likely conserved among MST2 homologs. Our works also highlights potential differences in Hippo signal propagation between each activating event owing to differences in the dynamics and regulation of each protein ensemble that triggers MST2 autophosphorylation and possible redundancy in activation.

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“…Interestingly, the structural analysis of InsP 6 /PH domain complex showed that the PH domain of Btk has two InsP 6 binding sites (21). The occupation of both sites in PH domain is important for the activation of Btk by dimerization (21,53). One of them is a canonical binding site that is essential for binding to PtdIP 3 in the membrane.…”

Section: Discussionmentioning

confidence: 99%

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

Kim

Min

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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T cell-independent (TI) B cell response is critical for the early protection against pathogen invasion. The regulation and activation of Bruton’s tyrosine kinase (Btk) is known as a pivotal step of B cell antigen receptor (BCR) signaling in TI humoral immunity, as observed in patients with X-linked agammaglobulinemia (XLA) experiencing a high incidence of encapsulated bacterial infections. However, key questions remain as to whether a well-established canonical BCR signaling pathway is sufficient to regulate the activity of Btk. Here, we find that inositol hexakisphosphate (InsP6) acts as a physiological regulator of Btk in BCR signaling. Absence of higher order inositol phosphates (InsPs), inositol polyphosphates, leads to an inability to mount immune response against TI antigens. Interestingly, the significance of InsP6-mediated Btk regulation is more prominent in IgM+plasma cells. Hence, the present study identifies higher order InsPs as principal components of B cell activation upon TI antigen stimulation and presents a mechanism for InsP-mediated regulation of the BCR signaling.

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Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization

Cited by 12 publications

References 52 publications

HIV-1 Nef dimers short-circuit immune receptor signaling by activating Tec-family kinases at the host cell membrane

HIV-1 Nef dimers short-circuit immune receptor signaling by activating Tec-family kinases at the host cell membrane

Increasing kinase domain proximity promotes MST2 autophosphorylation during Hippo signaling

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

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