Molecular dissection of the interaction between the SH3 domain and the SH2-Kinase Linker region in PTK6

Kim, Han Ie; Jung, Jinwon; Lee, Eun Saem; Kim, Yong Chul; Lee, Weontae; Lee, Seung Taek

doi:10.1016/j.bbrc.2007.08.055

Cited by 16 publications

(13 citation statements)

References 21 publications

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“…The kinase that phosphorylates the PTK6 C-terminal tyrosine has not been identified, although CSK (c-Src tyrosine Kinase) that phosphorylates the SRC C-terminal tyrosine probably does not phosphorylate PTK6 [16]. Interactions between the SH3 domain and the proline-rich linker region are also involved in autoinhibition [16,19,20] and are thought to stabilize the inactive state of the enzyme similar to SRC. The SH3 domain consists mainly of β-sheets, which exhibit a unique and folded structure at neutral pH that is sensitive to pH changes [21].…”

Section: Ptk6 Structurementioning

confidence: 99%

Building a better understanding of the intracellular tyrosine kinase PTK6 — BRK by BRK

Brauer

Tyner

2010

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

130

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Protein tyrosine kinase 6 (PTK6), also referred to as breast tumor kinase BRK, is a member of a distinct family of kinases that is evolutionarily related to the SRC family of tyrosine kinases. While not expressed in the normal mammary gland, PTK6 expression is detected in a large proportion of human mammary gland tumors. In breast tumor cells, PTK6 promotes growth factor signaling and cell migration. PTK6 expression is also increased in a number of other epithelial tumors, including ovarian and colon cancer. In contrast, PTK6 is expressed in diverse normal epithelia, including the linings of the gastrointestinal tract, skin and prostate, where its expression correlates with cell cycle exit and differentiation. Disruption of the mouse Ptk6 gene leads to increased growth and impaired differentiation in the small intestine that is accompanied by increased AKT and Wnt signaling. Following total body irradiation, PTK6 expression is induced in proliferating progenitor cells of the intestine, where it plays an essential role in DNA-damage induced apoptosis. A distinguishing feature of PTK6 is its flexibility in intracellular localization, due to a lack of amino-terminal myristoylation/ palmitoylation. Recently a number of substrates of PTK6 have been identified, including nuclear RNA-binding proteins and transcription factors. We discuss PTK6 signaling, its apparent conflicting roles in cancer and normal epithelia, and its potential as a therapeutic target in epithelial cancers.

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Section: Ptk6 Structurementioning

confidence: 99%

Building a better understanding of the intracellular tyrosine kinase PTK6 — BRK by BRK

Brauer

Tyner

2010

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

130

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“…Although distinct from Src-family kinases, the intestinal kinase PTK6 is a nonreceptor tyrosine kinase evolutionarily related to Src-family kinases. PTK6 shares common motifs with Src including SH2 and SH3 (Src-homology) domains [19,20], and is regulated in a similar manner in that a C-terminal tyrosine residue (Y447) negatively regulates its kinase activity by binding to the SH2 domain when phosphorylated [21]. In addition, PTK6 autophosphorylates residue Y342 which activates the kinase.…”

Section: Introductionmentioning

confidence: 99%

Protein tyrosine kinase 6 mediates TNFα-induced endothelial barrier dysfunction

Haines

Beard

2015

Biochemical and Biophysical Research Communications

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A key event in the progression of systemic inflammation resulting from severe trauma or shock involves microvascular hyperpermeability, which leads to excessive plasma fluid and proteins accumulating in extravascular space resulting in tissue edema. The precise molecular mechanism of the hyperpermeability response is not completely understood. Protein tyrosine kinase 6 (PTK6, also known as breast tumor kinase BRK) is a non-receptor tyrosine kinase related to Src-family proteins. Although it has also been shown that PTK6 participates in regulating epithelial barrier function, the role of PTK6 in endothelial barrier function has not been reported. In this study, we hypothesized that PTK6 is 1) expressed in vascular endothelial cells, and 2) contributes to vascular endothelial hyperpermeability in response to TNFα. Results showed that PTK6 was detected in mouse endothelial cells at the level of protein and mRNA. In addition, PTK6 knockdown attenuated TNFα induced decrease in endothelial barrier function as measured by electric cell-substrate impedance sensing (ECIS) and in vitro transwell albumin-flux assays. Furthermore, we showed that TNFα treatment of endothelial cells increased active PTK6 association with p120-catenin at endothelial cell-cell junctions. Further analysis using immunocytochemistry and immunoprecipitation demonstrated that PTK6 knockdown attenuated TNFα induced VE-cadherin internalization as well as promoting its association with p120-catenin. Our study demonstrates a novel role of PTK6 in mediating endothelial barrier dysfunction.

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“…For instance, we have previously shown that the residues in the SH3 domain interact with those in the Linker region, resulting auto-inhibition of the PTK6 activity. 12,13 Since the biological role of the SH32L of PTK6 is still unclear despite the structural homology with those of other family proteins, three-dimensional structural information together with biological data would be of importance in understanding the molecular function of PTK6. Therefore, our report from this study will contribute for detailed structure-functional investigation of the SH32L domain and multi-dimensional NMR experiments to determine the detailed three-dimensional structure of the SH32L are currently in progress.…”

Section: Resultsmentioning

confidence: 99%

“…8,9 In addition, we proposed that the SH3 domain of PTK6 interacts with the linker region between the SH2 and kinase domains and a Trp 44 residue in the SH3 domain plays a key role in the intra-molecular interaction with proline-rich linker region by data from site-directed mutagenesis and surface plasmon resonance experiments. [10][11][12][13] Since the interaction between SH3 domain and linker region is mainly responsible for both auto-inhibitory and substrate binding mechanism, it is of interest to characterize detailed structural information between SH3-SH2 domain and linker region. Here, we present the molecular cloning and NMR characterization of the SH3-SH2-linker domain (SH32L) for further structural and biochemical analysis related to auto-inhibitory mechanism of the non receptor tyrosine kinase, PTK6.…”

Section: Introductionmentioning

confidence: 99%

Molecular Cloning and NMR Characterization of the Nonreceptor Tyrosine Kinase PTK6 SH3-SH2-Linker Domain

Lee

Ahn

et al. 2009

Bulletin of the Korean Chemical Society

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1Human protein tyrosine kinase-6 (PTK6) is a member of the non-receptor protein tyrosine kinase family and it is found in two-thirds of all breast tumors. Very recently, we proposed that the SH3 domain of PTK6 interacts with the linker region (Linker) between the SH2 and kinase domains, proving that the interaction between SH3 domain and Linker plays an important role in auto-inhibition mechanism. Residues from 1 to 191 corresponding region of SH3-SH2-Linker (SH32L) of PTK6 was cloned into the pET32a expression vector with Tobbaco etch virus (TEV) protease enzyme site by sequence homology and 3D structural model. The purified PTK6-SH32L was determined as a monomer conformation in solution. The amide proton resonances in the 15 N-1 H 2D-HSQC spectrum suggest that PTK6-SH32L possesses disordered structural region of the flexible/unstructured linker region. In addition, the backbone amide proton chemical shifts of the SH3 domain in the PTK6-SH32L differ from that of the independent domain, indicating that intra-molecular interaction between SH3 and Linker in the PTK6-SH32L is present.

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Molecular dissection of the interaction between the SH3 domain and the SH2-Kinase Linker region in PTK6

Cited by 16 publications

References 21 publications

Building a better understanding of the intracellular tyrosine kinase PTK6 — BRK by BRK

Building a better understanding of the intracellular tyrosine kinase PTK6 — BRK by BRK

Protein tyrosine kinase 6 mediates TNFα-induced endothelial barrier dysfunction

Molecular Cloning and NMR Characterization of the Nonreceptor Tyrosine Kinase PTK6 SH3-SH2-Linker Domain

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