Tyrosine Phosphorylation Regulates Maturation of Receptor Tyrosine Kinases

Schmidt-Arras, Dirk; Böhmer, Annette; Markova, Boyka; Choudhary, Chunaram; Serve, Hubert; Böhmer, Frank‐D.

doi:10.1128/mcb.25.9.3690-3703.2005

Cited by 134 publications

(182 citation statements)

References 47 publications

(38 reference statements)

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“…Under these conditions the PTP1B D/A trapping mutant failed to localize with the unstimulated Met receptor. This is in agreement with the ability of PTP1B D/A to engage with receptors within the synthetic pathway (62). Significantly, after stimulation with HGF, PTP1B D/A, but not the GFP vector or PTP1B WT, was observed in peripheral puncta with the Met receptor at 5Ј post-stimulation ( Fig.…”

Section: Ptp1b D/a Trapping Mutant Colocalizes With An Activated Metsupporting

confidence: 74%

“…PTP1B possesses an ER-targeting signal and localizes to the ER (22,61). A role for PTP1B has been proposed in the dephosphorylation of RTKs after stimulation (18) as well as from the synthetic pathway (62). To examine the colocalization of Met and PTP1B in the absence of stimulation, HeLa cells were transfected with GFP-tagged WT or the substrate trapping mutant of PTP1B (D/A), and their localization was analyzed by confocal microscopy.…”

Section: Ptp1b D/a Trapping Mutant Colocalizes With An Activated Metmentioning

confidence: 99%

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Regulation of the Met Receptor-tyrosine Kinase by the Protein-tyrosine Phosphatase 1B and T-cell Phosphatase

Sangwan

Paliouras

Abella

et al. 2008

Journal of Biological Chemistry

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The non-receptor protein-tyrosine phosphatases (PTPs) 1B and T-cell phosphatase (TCPTP) have been implicated as negative regulators of multiple signaling pathways including receptor-tyrosine kinases. We have identified PTP1B and TCPTP as negative regulators of the hepatocyte growth factor receptor, the Met receptor-tyrosine kinase. In vivo, loss of PTP1B or TCPTP enhances hepatocyte growth factor-mediated phosphorylation of Met. Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain. Using confocal microscopy, we show that trapping mutants of both PTP1B and the endoplasmic reticulumtargeted TCPTP isoform, TC48, colocalize with Met and that activation of Met enables the nuclear-localized isoform of TCPTP, TC45, to exit the nucleus. Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases. This enhanced phosphorylation of Met corresponds to enhanced biological activity and cellular invasion. Our data demonstrate that PTP1B and TCPTP play distinct and non-redundant roles in the regulation of the Met receptor-tyrosine kinase.The receptor for hepatocyte growth factor/scatter factor, Met, controls a program of epithelial growth and remodeling through the coordination of cell proliferation and survival, cell migration, and epithelial morphogenesis (1). This process is important both during embryogenesis and for organ regeneration in the adult (2-4). In response to HGF 5 binding, the catalytic kinase activity of the Met receptor is elevated, leading to intermolecular autophosphorylation and recruitment of signaling molecules. These, through a series of protein-protein interactions, transduce the extracellular signal to the interior of the cell. Although numerous studies have addressed mechanisms resulting in elevation of Met RTK activity (5), little is known about the mechanisms involved in down-regulation of the Met receptor.Biological consequences resulting from RTK activation are determined by the duration, intensity, and specificity of the signals activated downstream of the receptor. Regulation of signals occurs on multiple levels, including the RTK itself. Ligand activation of the Met receptor promotes internalization of the receptor into the endocytic pathway with subsequent degradation in the lysosome (6). Termination of RTK signaling has been correlated with receptor dephosphorylation, degradation, or sequestration from the cytoplasm (5). In addition to receptor internalization, trafficking, and degradation in the lysosome as mechanisms of down-regulation, the Met receptor has been identified as a substrate for several PTPs. The receptor PTP LAR (leukocyte antigen-related) targets the Met receptor in confluent cells. This interac...

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Section: Ptp1b D/a Trapping Mutant Colocalizes With An Activated Metsupporting

confidence: 74%

Section: Ptp1b D/a Trapping Mutant Colocalizes With An Activated Metmentioning

confidence: 99%

Regulation of the Met Receptor-tyrosine Kinase by the Protein-tyrosine Phosphatase 1B and T-cell Phosphatase

Sangwan

Paliouras

Abella

et al. 2008

Journal of Biological Chemistry

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“…We also observed a higher frequency of LT-HSC in KLI chimeras (Supplementary Figure 4F). However, there is evidence that Flt3 ITD/ þ mice have lower surface expression of the FLT3 receptor (Jacobsen, personal communication) probably due to entrapment of the FLT3 ITD in the endoplasmic reticulum 25,26 and therefore identification of LT-and ST-HSC using FLT3 may be problematic. Consequently, we decided to rely on expression of CD150 and CD48 (Figures 3a and b) to identify LT-HSC (LSKCD150 þ CD48 À ) and MPP (CD150 À CD48 þ ).…”

Section: Resultsmentioning

confidence: 99%

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

et al. 2012

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Biallelic CEBPA mutations and FMS-like tyrosine kinase receptor 3 (FLT3) length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear because of a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of an internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed CCAAT/enhancer binding protein alpha (C/EBPa) mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMPs) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPa mutations. These cellular changes are accompanied by an upregulation of hematopoietic stem cell and STAT5 target genes. By gene expression analysis in premalignant populations, we further show a role of FLT3 ITD in activating genes involved in survival/transformation and chemoresistance. Both multipotent progenitors and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.

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“…For immunostaining, cells were directly fixed in 2% paraformaldehyde, permeabilized with ethanol, and stained with primary antibodies for 12 hours followed by labeled secondary antibodies. 40,41 The primary antibodies used were as follows: anti-Fms rat IgG (clone 3-4A4-E4; Abcam, Cambridge, MA), anti-GM130 mouse IgG (Transduction Laboratories), anti-CD8 rabbit IgG (H-160; Santa Cruz Biotechnology), and rabbit IgG specific for Hck phosphorylated at Tyr411 (Santa Cruz Biotechnology). The labeled secondary antibodies used were as follows: anti-rat IgG-AlexaFluo488, anti-mouse IgG-AlexaFluo568, and anti-rabbit IgG-AlexaFluo488 (Molecular Probes, Eugene, OR).…”

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confidence: 99%

Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor

Hiyoshi¹,

Suzu²,

Yoshidomi³

et al. 2008

Blood

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Nef is a multifunctional pathogenetic protein of HIV-1, the interaction of which with Hck, a Src tyrosine kinase highly expressed in macrophages, has been shown to be responsible for the development of AIDS. However, how the Nef-Hck interaction leads to the functional aberration of macrophages is poorly understood. We recently showed that Nef markedly inhibited the activity of macrophage colonystimulating factor (M-CSF), a primary cytokine for macrophages. Here IntroductionHIV-1 infections lead to the development of AIDS by causing progressive degeneration of the immune system. [1][2][3] The main cellular targets of HIV-1 are CD4 ϩ T cells and macrophages, and the depletion of CD4 ϩ T cells caused by an infection is suggested to account for many aspects of the pathogenesis of HIV-1. [1][2][3] Meanwhile, a number of studies have revealed the functional aberration of HIV-1-infected macrophages. 4,5 Infected macrophages showed an altered profile of the production of cytokine/chemokines 4 or migratory capacity, 5 which might contribute to the uncontrolled homeostasis of the immune system. Indeed, functional analyses of HIV-1 Nef protein have revealed that macrophages as well as CD4 ϩ T cells play an important role in the development of AIDS.Nef is a 25-to 30-kDa protein with no enzymatic activity encoded by the HIV-1 genome. 6,7 Studies of HIV-1-infected patients have clearly demonstrated Nef to be a critical determinant of the development of AIDS: HIV-1 strains without an intact Nef gene were frequently isolated from nonprogressive long-term survivors. 8,9 Subsequent study of HIV-1 transgenic mice confirmed the pathogenetic activity of Nef: targeted expression of the entire coding sequence of HIV-1 in CD4 ϩ T cells and macrophages caused a severe AIDS-like disease in mice, which was completely abolished by the disruption of the Nef gene. 10 Importantly, only an amino acid substitution in the proline-rich (PxxP) motifs of Nef was sufficient to protect mice from the development of AIDS-like disease. 11 A number of studies have revealed that Nef interacts with a subset of cellular Src family tyrosine kinases, via the PxxP motifs. 12-15 The Nef PxxP motifs had an affinity for the Src homology (SH3) domain of Hck, Lyn, and possibly c-Src, but not of Fgr, Fyn, Lck, In particular, the interaction between the Nef PxxP motifs and the Hck SH3 domain was likely to be important, because the interaction caused the activation of Hck. [13][14][15] Indeed, a study with HIV-1 transgenic mice clearly demonstrated the importance of the Nef-Hck interaction for the development of AIDS: the appearance of the AIDS-like disease was significantly delayed when the HIV-1 transgenic mice expressing an intact Nef gene were crossed with an hck Ϫ/Ϫ background. 11 Given that Hck is expressed in macrophages but not in CD4 ϩ T cells, 16 the finding indicates that the Nef-Hck interaction in macrophages is at least in part responsible for the development of AIDS. However, little is known of the molecular mechanisms by which the Nef-Hck interaction c...

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Tyrosine Phosphorylation Regulates Maturation of Receptor Tyrosine Kinases

Cited by 134 publications

References 47 publications

Regulation of the Met Receptor-tyrosine Kinase by the Protein-tyrosine Phosphatase 1B and T-cell Phosphatase

Regulation of the Met Receptor-tyrosine Kinase by the Protein-tyrosine Phosphatase 1B and T-cell Phosphatase

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor

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