scholarly journals Negative Regulation of Ros Receptor Tyrosine Kinase Signaling

2001 ◽  
Vol 152 (2) ◽  
pp. 325-334 ◽  
Author(s):  
Heike Keilhack ◽  
Marit Müller ◽  
Sylvia-Annette Böhmer ◽  
Carsten Frank ◽  
K. Michael Weidner ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Glutathione S Transferase ◽  
Tyrosine Kinase Signaling ◽  
Ros Signaling ◽  
Targeted Inactivation

Male “viable motheaten” (mev) mice, with a naturally occurring mutation in the gene of the SH2 domain protein tyrosine phosphatase SHP-1, are sterile. Known defects in sperm maturation in these mice correlate with an impaired differentiation of the epididymis, which has similarities to the phenotype of mice with a targeted inactivation of the Ros receptor tyrosine kinase. Ros and SHP-1 are coexpressed in epididymal epithelium, and elevated phosphorylation of Ros in the epididymis of mev mice suggests that Ros signaling is under control of SHP-1 in vivo. Phosphorylated Ros strongly and directly associates with SHP-1 in yeast two-hybrid, glutathione S-transferase pull-down, and coimmunoprecipitation experiments. Strong binding of SHP-1 to Ros is selective compared to six other receptor tyrosine kinases. The interaction is mediated by the SHP-1 NH2-terminal SH2 domain and Ros phosphotyrosine 2267. Overexpression of SHP-1 results in Ros dephosphorylation and effectively downregulates Ros-dependent proliferation and transformation. We propose that SHP-1 is an important downstream regulator of Ros signaling.

scholarly journals The Selectivity of Receptor Tyrosine Kinase Signaling Is Controlled by a Secondary SH2 Domain Binding Site

Cell ◽  
2009 ◽  
Vol 138 (3) ◽  
pp. 514-524 ◽  
Author(s):  
Jae Hyun Bae ◽  
Erin Denise Lew ◽  
Satoru Yuzawa ◽  
Francisco Tomé ◽  
Irit Lax ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Binding Site ◽  
Receptor Tyrosine Kinase ◽  
Sh2 Domain ◽  
Kinase Signaling ◽  
Tyrosine Kinase Signaling

scholarly journals Mutagenic analysis of the roles of SH2 and SH3 domains in regulation of the Abl tyrosine kinase.

1994 ◽  
Vol 14 (5) ◽  
pp. 2883-2894 ◽  
Author(s):  
B J Mayer ◽  
D Baltimore
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Sh3 Domain ◽  
Sh2 Domain ◽  
Sh3 Domains ◽  
Sh2 Domains ◽  
Abl Tyrosine Kinase ◽  
Transforming Activity

We have used in vitro mutagenesis to examine in detail the roles of two modular protein domains, SH2 and SH3, in the regulation of the Abl tyrosine kinase. As previously shown, the SH3 domain suppresses an intrinsic transforming activity of the normally nontransforming c-Abl product in vivo. We show here that this inhibitory activity is extremely position sensitive, because mutants in which the position of the SH3 domain within the protein is subtly altered are fully transforming. In contrast to the case in vivo, the SH3 domain has no effect on the in vitro kinase activity of the purified protein. These results are consistent with a model in which the SH3 domain binds a cellular inhibitory factor, which in turn must physically interact with other parts of the kinase. Unlike the SH3 domain, the SH2 domain is required for transforming activity of activated Abl alleles. We demonstrate that SH2 domains from other proteins (Ras-GTPase-activating protein, Src, p85 phosphatidylinositol 3-kinase subunit, and Crk) can complement the absence of the Abl SH2 domain and that mutants with heterologous SH2 domains induce altered patterns of tyrosine-phosphorylated proteins in vivo. The positive function of the SH2 domain is relatively position independent, and the effect of multiple SH2 domains appears to be additive. These results suggest a novel mechanism for regulation of tyrosine kinases in which the SH2 domain binds to, and thereby enhances the phosphorylation of, a subset of proteins phosphorylated by the catalytic domain. Our data also suggest that the roles of the SH2 and SH3 domains in the regulation of Abl are different in several respects from the roles proposed for these domains in the closely related Src family of tyrosine kinases.

Signalling by the W/Kit receptor tyrosine kinase is negatively regulated in vivo by the protein tyrosine phosphatase Shp1

1996 ◽  
Vol 13 (3) ◽  
pp. 309-315 ◽  
Author(s):  
Robert F. Paulson ◽  
Shirly Vesely ◽  
Katharine A. Siminovitch ◽  
Alan Bernstein
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine ◽  
Kit Receptor

scholarly journals A vesicle surface tyrosine kinase regulates phagosome maturation

2007 ◽  
Vol 178 (3) ◽  
pp. 411-423 ◽  
Author(s):  
Jun Fang ◽  
Joseph A. Brzostowski ◽  
Stephen Ou ◽  
Nilgun Isik ◽  
Vinod Nair ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Control Mechanism ◽  
Kinase Domain ◽  
Microbial Pathogens ◽  
Phagosome Maturation ◽  
Tyrosine Kinase Signaling ◽  
Late Endosomes

Phagocytosis is crucial for host defense against microbial pathogens and for obtaining nutrients in Dictyostelium discoideum. Phagocytosed particles are delivered via a complex route from phagosomes to lysosomes for degradation, but the molecular mechanisms involved in the phagosome maturation process are not well understood. Here, we identify a novel vesicle-associated receptor tyrosine kinase-like protein, VSK3, in D. discoideum. We demonstrate how VSK3 is involved in phagosome maturation. VSK3 resides on the membrane of late endosomes/lysosomes with its C-terminal kinase domain facing the cytoplasm. Inactivation of VSK3 by gene disruption reduces the rate of phagocytosis in cells, which is rescued by re-expression of VSK3. We found that the in vivo function of VSK3 depends on the presence of the kinase domain and vesicle localization. Furthermore, VSK3 is not essential for engulfment, but instead, is required for the fusion of phagosomes with late endosomes/lysosomes. Our findings suggest that localized tyrosine kinase signaling on the surface of endosome/lysosomes represents a control mechanism for phagosome maturation.

The SH2-containing tyrosine phosphatase corkscrew is required during signaling by sevenless, Ras1 and Raf

Development ◽  
1996 ◽  
Vol 122 (4) ◽  
pp. 1137-1146 ◽  
Author(s):  
J.D. Allard ◽  
H.C. Chang ◽  
R. Herbst ◽  
H. McNeill ◽  
M.A. Simon
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Protein Tyrosine Phosphatase ◽  
Photoreceptor Cell ◽  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Genetic Screen ◽  
Parallel Pathway ◽  
Photoreceptor Development

The sevenless gene encodes a receptor tyrosine kinase which is required for the development of the R7 photoreceptor cell in each ommatidium of the Drosophila eye. We have previously used a sensitized genetic screen to identify mutations, designated Enhancers of sevenless (E(sev)), which affect genes that encode components of the sevenless signaling pathway. Here, we report that one of these mutations, E(sev)1Ae0P is a dominantly inhibiting allele of corkscrew, which encodes an SH2 domain-containing protein tyrosine phosphatase (Perkins et al., 1992). We show that corkscrew function is essential for sevenless signaling and that expression of a membrane-targeted form of corkscrew can drive R7 photoreceptor development in the absence of sevenless function. Furthermore, we have used the dominantly inhibiting corkscrew allele to examine the role of corkscrew during signaling by activated forms of Ras1 and Raf. Our analysis indicates that corkscrew function is still required during signaling by activated forms Ras1 and Raf proteins. These results define a function for corkscrew that is either downstream of Ras1 activation or in a parallel pathway that acts with activated Ras1/Raf to specify R7 photoreceptor development.

scholarly journals Mutagenic analysis of the roles of SH2 and SH3 domains in regulation of the Abl tyrosine kinase

1994 ◽  
Vol 14 (5) ◽  
pp. 2883-2894
Author(s):  
B J Mayer ◽  
D Baltimore
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Sh3 Domain ◽  
Sh2 Domain ◽  
Sh3 Domains ◽  
Sh2 Domains ◽  
Abl Tyrosine Kinase ◽  
Transforming Activity

We have used in vitro mutagenesis to examine in detail the roles of two modular protein domains, SH2 and SH3, in the regulation of the Abl tyrosine kinase. As previously shown, the SH3 domain suppresses an intrinsic transforming activity of the normally nontransforming c-Abl product in vivo. We show here that this inhibitory activity is extremely position sensitive, because mutants in which the position of the SH3 domain within the protein is subtly altered are fully transforming. In contrast to the case in vivo, the SH3 domain has no effect on the in vitro kinase activity of the purified protein. These results are consistent with a model in which the SH3 domain binds a cellular inhibitory factor, which in turn must physically interact with other parts of the kinase. Unlike the SH3 domain, the SH2 domain is required for transforming activity of activated Abl alleles. We demonstrate that SH2 domains from other proteins (Ras-GTPase-activating protein, Src, p85 phosphatidylinositol 3-kinase subunit, and Crk) can complement the absence of the Abl SH2 domain and that mutants with heterologous SH2 domains induce altered patterns of tyrosine-phosphorylated proteins in vivo. The positive function of the SH2 domain is relatively position independent, and the effect of multiple SH2 domains appears to be additive. These results suggest a novel mechanism for regulation of tyrosine kinases in which the SH2 domain binds to, and thereby enhances the phosphorylation of, a subset of proteins phosphorylated by the catalytic domain. Our data also suggest that the roles of the SH2 and SH3 domains in the regulation of Abl are different in several respects from the roles proposed for these domains in the closely related Src family of tyrosine kinases.

scholarly journals Structural Determinants of SHP-2 Function and Specificity in Xenopus Mesoderm Induction

1998 ◽  
Vol 18 (1) ◽  
pp. 161-177 ◽  
Author(s):  
Alana M. O’Reilly ◽  
Benjamin G. Neel
Keyword(s):  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Negative Regulator ◽  
Mesoderm Induction ◽  
Structural Determinants ◽  
Tyrosine Kinase Signaling ◽  
Biologically Relevant ◽  
Sh2 Domains ◽  
Tyrosyl Phosphorylation

ABSTRACT SHP-2 is a positive component of many receptor tyrosine kinase signaling pathways. The related protein-tyrosine phosphatase (PTP) SHP-1 usually acts as a negative regulator. The precise domains utilized by SHP-2 to transmit positive signals in vivo and the basis for specificity between SHP-1 and SHP-2 are not clear. InXenopus, SHP-2 is required for mesoderm induction and completion of gastrulation. We investigated the effects of SHP-2 mutants and SHP-2/SHP-1 chimeras on basic fibroblast growth factor-induced mesoderm induction. Both SH2 domains and the PTP domain are required for normal SHP-2 function in this pathway. The N-terminal SH2 domain is absolutely required, whereas the C-terminal SH2 contributes to wild-type function. The C-terminal tyrosyl phosphorylation sites and proline-rich region are dispensable, arguing against adapter models of SHP-2 function. Although the SH2 domains contribute to SHP-2 specificity, studies of SHP chimeras reveal that substantial specificity resides in the PTP domain. Thus, PTP domains exhibit biologically relevant specificity in vivo, and noncatalytic and catalytic domains of PTPs contribute to specificity in a combinatorial fashion.

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