Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction.

The JNK (c-Jun N-terminal kinase) pathway is activated by diverse stresses and can have an effect on a number of different cellular processes. Protein–protein interactions are critical for efficient signalling from JNK to multiple targets; through a screen for interacting proteins, we identified a novel JNK-interacting protein, Sab (SH3BP5). Sab has previously been found to interact with the Src homology 3 domain of Bruton's tyrosine kinase; however, the interaction with JNK occurs through a mitogen-activated protein KIM (kinase interaction motif) in a region distinct from the Bruton's tyrosine kinase-binding domain. As with c-Jun, the presence of this KIM is essential for Sab to act as a JNK substrate. Interestingly, Sab is associated with the mitochondria and co-localizes with a portion of active JNK after stress treatment. The present study and previously reported work may suggest a possible role for Sab in targeting JNK to this subcellular compartment and/or mediating crosstalk between different signal-transduction pathways.

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Regulation of Cdc42 Gtpase by Proline-Rich Tyrosine Kinase 2 Interacting with Psgap, a Novel Pleckstrin Homology and Src Homology 3 Domain Containing Rhogap Protein

The Journal of Cell Biology ◽

10.1083/jcb.152.5.971 ◽

2001 ◽

Vol 152 (5) ◽

pp. 971-984 ◽

Cited By ~ 78

Author(s):

Xiu-Rong Ren ◽

Quan-Sheng Du ◽

Yang-Zhong Huang ◽

Shi-Zhou Ao ◽

Lin Mei ◽

...

Keyword(s):

Tyrosine Kinase ◽

Pleckstrin Homology Domain ◽

Cell Periphery ◽

Dependent Manner ◽

Pleckstrin Homology ◽

Cytoskeletal Organization ◽

Src Homology 3 ◽

Tyrosine Kinase 2 ◽

Src Homology 3 Domain ◽

Src Homology

Proline-rich tyrosine kinase 2 (PYK2), a tyrosine kinase structurally related to focal adhesion kinase (FAK), is implicated in regulating cytoskeletal organization. However, mechanisms by which PYK2 participates in and regulates cytoskeletal organization remain largely unknown. Here we report identification of PSGAP, a novel protein that interacts with PYK2 and FAK and contains multiple domains including a pleckstrin homology domain, a rhoGTPase-activating protein domain, and a Src homology 3 domain. PYK2 interacts with PSGAP Src homology 3 domain via the carboxyl-terminal proline-rich sequence. PSGAP is able to increase GTPase activity of CDC42 and RhoA in vitro and in vivo. Remarkably, PYK2, but not FAK, can activate CDC42 via inhibition of PSGAP-mediated GTP hydrolysis of CDC42. Moreover, PSGAP is localized at cell periphery in fibroblasts in a pleckstrin homology domain–dependent manner. Over expression of PSGAP in fibroblasts results in reorganization of cytoskeletal structures and changes of cellular morphology, which requires rhoGTPase-activating activity. Taken together, our results suggest that PSGAP is a signaling protein essential for PYK2 regulation of cytoskeletal organization via Rho family GTPases.

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The activation mechanism of ACK1 (activated Cdc42-associated tyrosine kinase 1)

Biochemical Journal ◽

10.1042/bj20111575 ◽

2012 ◽

Vol 445 (2) ◽

pp. 255-264 ◽

Cited By ~ 19

Author(s):

Qiong Lin ◽

Jian Wang ◽

Chandra Childress ◽

Wannian Yang

Keyword(s):

Cell Adhesion ◽

Growth Factor ◽

Tyrosine Kinase ◽

Molecular Mechanism ◽

Growth Factor Receptor ◽

Activation Mechanism ◽

Src Homology 3 ◽

Src Homology 3 Domain ◽

Src Homology ◽

Epidermal Growth

ACK [activated Cdc42 (cell division cycle 42)-associated tyrosine kinase; also called TNK2 (tyrosine kinase, non-receptor, 2)] is activated in response to multiple cellular signals, including cell adhesion, growth factor receptors and heterotrimeric G-protein-coupled receptor signalling. However, the molecular mechanism underlying activation of ACK remains largely unclear. In the present study, we demonstrated that interaction of the SH3 (Src homology 3) domain with the EBD [EGFR (epidermal growth factor receptor)-binding domain] in ACK1 forms an auto-inhibition of the kinase activity. Release of this auto-inhibition is a key step for activation of ACK1. Mutation of the SH3 domain caused activation of ACK1, independent of cell adhesion, suggesting that cell adhesion-mediated activation of ACK1 is through releasing the auto-inhibition. A region at the N-terminus of ACK1 (Leu10–Leu14) is essential for cell adhesion-mediated activation. In the activation of ACK1 by EGFR signalling, Grb2 (growth-factor-receptor-bound protein 2) mediates the interaction of ACK1 with EGFR through binding to the EBD and activates ACK1 by releasing the auto-inhibition. Furthermore, we found that mutation of Ser445 to proline caused constitutive activation of ACK1. Taken together, our studies have revealed a novel molecular mechanism underlying activation of ACK1.

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