Identification of Rlk, a Novel Protein Tyrosine Kinase with Predominant Expression in the T Cell Lineage

Hu, Qiongzheng; Davidson, David; Schwartzberg, Pamela L.; Macchiarini, Francesca; Lenardo, Michael J.; Bluestone, Jeffrey A.; Matis, Louis A.

doi:10.1074/jbc.270.4.1928

Cited by 85 publications

(64 citation statements)

References 39 publications

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“…The subsequent molecular cloning of four Tec-related kinases, Btk (2,3), Itk (also known as Emt or Tsk) (4-6), Bmx (7), and Txk (or Rlk) (8,9), revealed that these enzymes, together with Tec, constitute a distinct subfamily of nonreceptor PTKs. With the exception of Txk, the members of this subfamily possess a long NH 2 -terminal region consisting of a pleckstrin homology (PH) domain (10) and a Tec homology (TH) domain (11).…”

mentioning

confidence: 99%

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

Ohya

Kajigaya

Kitanaka

et al. 1999

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

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mentioning

confidence: 99%

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

Ohya

Kajigaya

Kitanaka

et al. 1999

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

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“…Inducible T cell kinase (ITK) (1-5) belongs to the Tec family of nonreceptor protein tyrosine kinases, which includes Tec I and II (6,7), Bmx (8), Txk͞Rlk (9,10), and Bruton's tyrosine kinase (BTK) (11,12). ITK is expressed primarily in T cells (1-3, 5), with some expression detected in natural killer cells (4).…”

mentioning

confidence: 99%

Src-induced activation of inducible T cell kinase (ITK) requires phosphatidylinositol 3-kinase activity and the Pleckstrin homology domain of inducible T cell kinase

August

Sadra

Dupont

et al. 1997

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

165

153

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The Tec family of tyrosine kinases are involved in signals emanating from cytokine receptors, antigen receptors, and other lymphoid cell surface receptors. One family member, ITK (inducible T cell kinase), is involved in T cell activation and can be activated by the T cell receptor and the CD28 cell surface receptor. This stimulation of tyrosine phosphorylation and activation of ITK can be mimicked by the Src family kinase Lck. We have explored the mechanism of this requirement for Src family kinases in the activation of ITK. We found that coexpression of ITK and Src results in increased membrane association, tyrosine phosphorylation and activation of ITK, which could be blocked by inhibitors of the lipid kinase phosphatidylinositol 3-kinase (PI 3-kinase) as well as overexpression of the p85 subunit of PI 3-kinase. Removal of the Pleckstrin homology domain (PH) of ITK resulted in a kinase that could no longer be induced to localize to the membrane or be activated by Src. The PH of ITK was also able to bind inositol phosphates phosphorylated at the D3 position. Membrane targeting of ITK without the PH recovered its ability to be activated by Src. These results suggest that ITK can be activated by a combination of Src and PI 3-kinase.Inducible T cell kinase (ITK) (1-5) belongs to the Tec family of nonreceptor protein tyrosine kinases, which includes Tec I and II (6, 7), Bmx (8), Txk͞Rlk (9, 10), and Bruton's tyrosine kinase (BTK) (11,12). ITK is expressed primarily in T cells (1)(2)(3)5), with some expression detected in natural killer cells (4). Mutations in BTK, found in B cells, have been shown to be responsible for human X-linked agammaglobulinemia and the murine X-linked immunodeficiency (11)(12)(13)(14). Similarly, mice lacking ITK have reduced numbers of mature thymocytes and reduced proliferative responses following T cell receptor (TcR) crosslinking (15). These reduced numbers in the absence of ITK suggest an important role for ITK in T cell development and function.ITK, while similar to that of the Src family of protein tyrosine kinases, differ from Src kinases in a number of respects. Like Src family kinases, it has Src homology 3 (SH3) and Src homology 2 (SH2) domains. However ITK lacks a negative regulatory tyrosine at the carboxy termini. ITK also has a proline-rich region, included in a Tec homology domain (TH), reported to interact with Src family kinase SH3 domains in vitro and in the yeast 2 hybrid (16). ITK, like the other Tec family members (except for Txk), also has a Pleckstrin homology domain (PH), which is not found in the Src family kinases. PHs have been shown to bind to inositol lipids in vitro (17) and are proposed to anchor their carriers to membrane lipids (18,19).Phosphatidylinositol 3-kinase (PI 3-kinase) is a lipid kinase that phosphorylates inositol lipids at the D3 position of the inositol ring (20). It is known that the serine͞threonine kinase ribosomal S-6 kinase (RSK) lies downstream of PI 3-kinase based on inhibition studies with PI 3-kinase inhibitors (21). Recently,...

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“…More recently, several studies showed that various PH domains bind to phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and inositol 1,4,5-trisphosphate (IP 3 ) through their positively charged residues in the amino-terminal four ␤-sheets (15,21,22). PIP 2 interactions with the amino-terminal PH domain of pleckstrin (21) and the PLC-␦1 PH domain (22) (30), and Txk/Rlk (31,32). In the present study we have characterized in detail the interaction between the Btk PH domain and PKC using an in vitro binding assay.…”

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confidence: 99%

Interactions between Protein Kinase C and Pleckstrin Homology Domains

Yao

Suzuki

Ozawa

et al. 1997

Journal of Biological Chemistry

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Pleckstrin homology (PH) domains comprised of loosely conserved sequences of ϳ100 amino acid residues are a functional protein motif found in many signal-transducing and cytoskeletal proteins. We recently demonstrated that the PH domains of Tec family protein-tyrosine kinases Btk and Emt (equal to Itk and Tsk) interact with protein kinase C (PKC) and that PKC down-regulates Btk by phosphorylation. In this study we have characterized the PKC-BtkPH domain interaction in detail. Using pure PKC preparations, it was shown that the Btk PH domain interacts with PKC with high affinity (K D ‫؍‬ 39 nM). Unlike other tested phospholipids, phosphatidylinositol 4,5-bisphosphate, which binds to several PH domains, competed with PKC for binding to the PH domain apparently because their binding sites on the amino-terminal portion of the PH domains overlap. The minimal PKC-binding sequence within the Btk PH domain was found to correspond roughly to the second and third ␤-sheets of the PH domains of known tertiary structures. On the other hand, the C1 regulatory region of PKC⑀ containing the pseudosubstrate and zinc finger-like sequences was found to be sufficient for strong binding to the Btk PH domain. Phorbol 12-myristate 13-acetate (PMA), a potent activator of PKC that interacts with the C1 region of PKC, inhibited the PKC-PH domain interaction, whereas the bioinactive PMA (4-␣-PMA) was ineffective. The isoform of PKC, which has a single zinc finger-like motif instead of the two tandem zinc finger-like sequences present in conventional and novel PKC isoforms, does not bind PMA. Thus, as expected, PH domain binding with PKC was not interfered with by PMA. Further, inhibitors that are known to attack the catalytic domains of serine/threonine kinases did not affect this PKC-PH domain interaction. In contrast, the presence of physiological concentrations of Ca 2؉ induced less than a 2-fold increase in PKC-PH domain binding. These results indicate that PKC binding to PH domains involve the ␤2-␤3 region of the Btk PH domain and the C1 region of PKC, and agents that interact with either of these regions (i.e. phosphatidylinositol 4,5-bisphosphate binding to the PH domain and PMA binding to the C1 region of PKC) might act to regulate PKC-PH domain binding.

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Identification of Rlk, a Novel Protein Tyrosine Kinase with Predominant Expression in the T Cell Lineage

Cited by 85 publications

References 39 publications

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

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

Src-induced activation of inducible T cell kinase (ITK) requires phosphatidylinositol 3-kinase activity and the Pleckstrin homology domain of inducible T cell kinase

Interactions between Protein Kinase C and Pleckstrin Homology Domains

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