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Beyond calcium: new signaling pathways for Tec family kinases

Aya Takesono, Lisa D. Finkelstein and Pamela L. Schwartzberg*

National Human Genome Research Institute, 49 Convent Drive, 49/4A38, National Institutes of Health, Bethesda, MD 20892, USA



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  		Fig. 1. The structure and interacting partners of Tec kinases. (a) The domain structure of the Tec family kinases. The PH domain is involved in protein-protein and protein-phospholipid interactions. The TH domain consists of a BH domain and a PR motif. The SH3 domain binds to proline-rich regions, and in collaboration with the SH2 domain it can engage the PR motif in an intramolecular interaction. The SH2 domain binds to phosphorylated tyrosine residues. The kinase domain has tyrosine-kinase catalytic activity. The atypical Tec kinase, Rlk/Txk, has a cysteinestring motif (Cys) instead of a PH domain and lacks the BH domain. Bmx/Etk lacks the PR motif of the TH domain and has an SH3-like domain. DSrc29 has two isoforms, one of which lacks the PH and TH domains. (b) Molecules that interact with the domains of Tec kinases. Both in vivo and in vitro detected interactions are included. Some binding partners have only been demonstrated for specific Tec kinases, and these are indicated in parentheses.

 


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  		Fig. 2. The two-step activation model for Tec kinases. (1) In the first step, the PH domain interacts with the products of PI3K or, alternatively, with other binding partners (such as the FERM domain of FAK, heterotrimeric G-protein subunits, PKCs or F-actin) to translocate to the plasma membrane or specific intracellular microenvironments required for activation. (2) Once at the membrane, Tec kinases are phosphorylated on a tyrosine residue in their catalytic domain by SFKs.

Subsequently, a tyrosine residue in the SH3 domain is autophosphorylated, preventing further inhibitory intramolecular interactions. Phosphorylated tyrosine residues are illustrated as red stars.

 


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  		Fig. 3. Involvement of Tec kinases in TCR signaling. The Tec kinases (represented here by Itk) are part of a signaling complex nucleated by LAT and SLP76 that is critical for the activation of PLC-{gamma}, Ca2+ mobilization, MAPK activation, as well as for downstream cytoskeletal rearrangements and transcriptional regulation. The red boxes represent phosphorylated ITAMs on the intracellular tails of the invariant TCR chains. Red circles represent actin. PIP2, PtdIns(4,5)P2; PIP3, PtdIns(3,4,5)P3.

 


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  		Fig. 4. Signals transmitted by Tec kinases. Genetic and biochemical studies have demonstrated that Tec kinases are activated by multiple membrane receptors and are involved in a variety of downstream responses including Ca2+ influx, apoptosis, gene expression, actin reorganization and adhesion/migration. These cell responses may influence each other, suggesting that the Tec kinases can broadly affect cellular physiology.

 

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© The Company of Biologists Ltd 2002