Molecular cloning of a docking protein, BRDG1, that acts downstream of the Tec tyrosine kinase

Ohya, Kazuhiro; Kajigaya, Sachiko; Kitanaka, Akira; Yoshida, Kōji; Miyazato, Akira; Yamashita, Yuichi; Yamanaka, Takeo; Ikeda, Uichi; Shimada, Kazuyuki; Ozawa, Keiya; Mano, Hiroyuki

doi:10.1073/pnas.96.21.11976

Cited by 58 publications

(59 citation statements)

References 39 publications

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“…BRDG1 (BCR downstream signaling 1), a docking protein containing a PH domain and proline-rich motifs, was identi®ed as a binding protein for the kinase domain of Tec by yeast two-hybrid system (Ohya et al, 1999). It was shown that BRDG1 is an in vivo substrate of Tec but not Btk or Etk/Bmx, indicating it is a speci®c substrate for Tec.…”

Section: Interaction With Brdg1mentioning

confidence: 99%

Signaling network of the Btk family kinases

Qiu¹,

2000

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The Btk family kinases represent new members of nonreceptor tyrosine kinases, which include Btk/Atk, Itk/ Emt/Tsk, Bmx/Etk, and Tec. They are characterized by having four structural modules: PH (pleckstrin homology) domain, SH3 (Src homology 3) domain, SH2 (Src homology 2) domain and kinase (Src homology 1) domain. Increasing evidence suggests that, like Srcfamily kinases, Btk family kinases play central but diverse modulatory roles in various cellular processes. They participate in signal transduction in response to virtually all types of extracellular stimuli which are transmitted by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen-receptors and integrins. They are regulated by many non-receptor tyrosine kinases such as Src, Jak, Syk and FAK family kinases. In turn, they regulate many of major signaling pathways including those of PI3K, PLCg and PKC. Both genetic and biochemical approaches have been used to dissect the signaling pathways and elucidate their roles in growth, di erentiation and apoptosis. An emerging new role of this family of kinases is cytoskeletal reorganization and cell motility. The physiological importance of these kinases was amply demonstrated by their link to the development of immunode®ciency diseases, due to germ-line mutations. The present article attempts to review the structure and functions of Btk family kinases by summarizing our current knowledge on the interacting partners associated with the di erent modules of the kinases and the diverse signaling pathways in which they are involved. Oncogene (2000) 19, 5651 ± 5661.

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Section: Interaction With Brdg1mentioning

confidence: 99%

Signaling network of the Btk family kinases

Qiu¹,

2000

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“…Selectivity of Active Compounds Regarding Different Substrates of Tec Kinase-To test whether the active compounds 6, 14, and 21 selectively block Tec-mediated tyrosine phosphorylation of FGF2, we tested another established substrate of Tec, STAP1 (48,49). In this independent set of experiments, the inhibitory potency of compounds 6, 14, and 21 toward Tecmediated FGF2 tyrosine phosphorylation was confirmed (Fig.…”

Section: Biochemical Characterization Of Fgf2 Binding To Tecmentioning

confidence: 97%

Small Molecule Inhibitors Targeting Tec Kinase Block Unconventional Secretion of Fibroblast Growth Factor 2

Venuta

Wegehingel

Sehr

et al. 2016

Journal of Biological Chemistry

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Fibroblast growth factor 2 (FGF2) is a potent mitogen promoting both tumor cell survival and tumor-induced angiogenesis. It is secreted by an unconventional secretory mechanism that is based upon direct translocation across the plasma membrane. Key steps of this process are (i) phosphoinositide-dependent membrane recruitment, (ii) FGF2 oligomerization and membrane pore formation, and (iii) extracellular trapping mediated by membrane-proximal heparan sulfate proteoglycans. Efficient secretion of FGF2 is supported by Tec kinase that stimulates membrane pore formation based upon tyrosine phosphorylation of FGF2. Here, we report the biochemical characterization of the direct interaction between FGF2 and Tec kinase as well as the identification of small molecules that inhibit (i) the interaction of FGF2 with Tec, (ii) tyrosine phosphorylation of FGF2 mediated by Tec in vitro and in a cellular context, and (iii) unconventional secretion of FGF2 from cells. We further demonstrate the specificity of these inhibitors for FGF2 because tyrosine phosphorylation of a different substrate of Tec is unaffected in their presence. Building on previous evidence using RNA interference, the identified compounds corroborate the role of Tec kinase in unconventional secretion of FGF2. In addition, they are valuable lead compounds with great potential for drug development aiming at the inhibition of FGF2-dependent tumor growth and metastasis.Although the majority of secretory proteins carry signal peptides for endoplasmic reticulum/Golgi-dependent secretion, a set of important growth factors and cytokines involved in tumor-induced angiogenesis and inflammatory responses makes use of alternative routes. These processes have collectively been termed "unconventional protein secretion" (1-5). FGF2 and IL1␤ are prominent examples for secretory proteins that make use of such pathways (4 -12). The molecular mechanism by which IL1␤ is secreted from cells is debated and may differ in some aspects between various kinds of immune cells (4,5,10,(13)(14)(15)(16). By contrast, the mechanism of the unconventional secretory pathway of FGF2 is emerging with great molecular detail (12). It is based upon direct translocation of folded species of FGF2 across plasma membranes (9,(17)(18)(19)(20). Hallmarks of this process are (i) FGF2 recruitment at the inner leaflet of the plasma membrane mediated by the phosphoinositide PI(4,5)P 2 2 (9, 21, 22), (ii) FGF2 oligomerization and membrane pore formation (11,12,23,24), and (iii) extracellular trapping of FGF2 mediated by membrane-proximal heparan sulfate proteoglycans (1,2,25,26). Recently, these hallmarks of FGF2 secretion have also been implicated in unconventional secretion of HIV-Tat (HIV trans-activator of transcription) (12, 27-30). Based on a genome-wide RNAi screening approach, two additional factors physically associated with the plasma membrane have been identified to play a role in FGF2 secretion, Tec kinase (9, 11, 12, 24, 31) and ATP1A1 (12, 32-34), the ␣ subunit of the Na/K-ATPase (35). Although t...

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“…Indeed, one of the isolated TIP clones, TIP4/BRDG1, turned out to be a phosphorylation-dependent binding protein to Tec (19). The pGAL4bd-TecKD plasmid was then used in the screening as described previously (19,20). The TIP6 cDNA obtained by the twohybrid screening was labeled with [␣-32 P]dCTP, and used as a probe to screen the K562 cDNA library which was constructed in the ZAP II phage vector (Stratagene, La Jolla, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Since this construct covers the ATP-binding site of Tec, the resultant fusion protein should have a PTK activity. Indeed, one of the isolated TIP clones, TIP4/BRDG1, turned out to be a phosphorylation-dependent binding protein to Tec (19). The pGAL4bd-TecKD plasmid was then used in the screening as described previously (19,20).…”

Section: Methodsmentioning

confidence: 99%

“…With the Tec kinase domain containing its ATP-binding site as a "bait," a total of six TIPs were identified from various cDNA expression libraries of human origin (19,20). Among them, TIP6 was isolated from a human cDNA library from bone marrow mononuclear cells, and its predicted amino acid sequence was highly homologous to the C-terminal portions of mouse Sak-a, raising the possibility that TIP6 is the human homologue of Sak-a.…”

Section: Identification Of Tip 6 As Humanmentioning

confidence: 99%

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Sak Serine-Threonine Kinase Acts as an Effector of Tec Tyrosine Kinase

Yamashita¹,

Yoshida²,

Ueno³

et al. 2001

Journal of Biological Chemistry

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The murine sak gene encodes a putative serine-threonine kinase which is homologous to the members of the Plk/Polo family. Although Sak protein is presumed to be involved in cell growth mechanism, efforts have failed to demonstrate its kinase activity. Little has been, therefore, elucidated how Sak is regulated and how Sak contributes to cell proliferation. Tec is a cytoplasmic protein-tyrosine kinase (

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Molecular cloning of a docking protein, BRDG1, that acts downstream of the Tec tyrosine kinase

Cited by 58 publications

References 39 publications

Signaling network of the Btk family kinases

Signaling network of the Btk family kinases

Small Molecule Inhibitors Targeting Tec Kinase Block Unconventional Secretion of Fibroblast Growth Factor 2

Sak Serine-Threonine Kinase Acts as an Effector of Tec Tyrosine Kinase

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