scholarly journals Binding, Domain Orientation, and Dynamics of the Lck SH3−SH2 Domain Pair and Comparison with Other Src-Family Kinases†

Biochemistry ◽  
2005 ◽  
Vol 44 (39) ◽  
pp. 13043-13050 ◽  
Author(s):  
Gregor Hofmann ◽  
Kristian Schweimer ◽  
Anke Kiessling ◽  
Edith Hofinger ◽  
Finn Bauer ◽  
...  
Keyword(s):  
Sh2 Domain ◽  
Src Family Kinases ◽  
Binding Domain ◽  
Domain Pair ◽  
Domain Orientation

scholarly journals SH3-SH2 Domain Orientation in Src Kinases

Structure ◽  
2002 ◽  
Vol 10 (7) ◽  
pp. 901-911 ◽  
Author(s):  
Tobias S Ulmer ◽  
Jörn M Werner ◽  
Iain D Campbell
Keyword(s):  
Sh2 Domain ◽  
Src Kinases ◽  
Domain Orientation

scholarly journals Tyrosine phosphorylation of BCR by FPS/FES protein-tyrosine kinases induces association of BCR with GRB-2/SOS.

1995 ◽  
Vol 15 (2) ◽  
pp. 835-842 ◽  
Author(s):  
Y Maru ◽  
K L Peters ◽  
D E Afar ◽  
M Shibuya ◽  
O N Witte ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Kinase ◽  
Sh2 Domain ◽  
Binding Domain ◽  
Ras Signaling ◽  
Cytoplasmic Protein ◽  
Nucleotide Exchange ◽  
Protein Tyrosine

The human bcr gene encodes a protein with serine/threonine kinase activity, CDC24/dbl homology, a GAP domain, and an SH2-binding region. However, the precise physiological functions of BCR are unknown. Coexpression of BCR with the cytoplasmic protein-tyrosine kinase encoded by the c-fes proto-oncogene in Sf-9 cells resulted in stable BCR-FES protein complex formation and tyrosine phosphorylation of BCR. Association involves the SH2 domain of FES and a novel binding domain localized to the first 347 amino acids of the FES N-terminal region. Deletion of the homologous N-terminal BCR-binding domain from v-fps, a fes-related transforming oncogene, abolished transforming activity and tyrosine phosphorylation of BCR in vivo. Tyrosine phosphorylation of BCR in v-fps-transformed cells induced its association with GRB-2/SOS, the RAS guanine nucleotide exchange factor complex. These data provide evidence that BCR couples the cytoplasmic protein-tyrosine kinase and RAS signaling pathways.

scholarly journals SRC is a signaling mediator in FLT3-ITD– but not in FLT3-TKD–positive AML

Blood ◽  
2012 ◽  
Vol 119 (17) ◽  
pp. 4026-4033 ◽  
Author(s):  
Hannes Leischner ◽  
Corinna Albers ◽  
Rebekka Grundler ◽  
Elena Razumovskaya ◽  
Karsten Spiekermann ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Point Mutations ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Src Family Kinases ◽  
Tyrosine Kinase Domain ◽  
Molecular Abnormalities ◽  
Flt3 Mutations ◽  
Worse Prognosis ◽  
Tandem Duplications

Abstract Mutations of Fms-like tyrosine kinase 3 (FLT3) are among the most frequently detected molecular abnormalities in AML patients. Internal tandem duplications (ITDs) are found in approximately 25% and point mutations within the second tyrosine kinase domain (TKD) in approximately 7% of AML patients. Patients carrying the FLT3-ITD but not the FLT3-TKD mutation have a significantly worse prognosis. Therefore, both FLT3 mutations seem to exert different biologic functions. FLT3-ITD but not FLT3-TKD has been shown to induce robust activation of the STAT5 signaling pathway. In the present study, we investigated the mechanisms leading to differential STAT5 activation and show that FLT3-ITD but not FLT3-TKD uses SRC to activate STAT5. Coimmunoprecipitation and pull-down experiments revealed an exclusive interaction between SRC but not other Src family kinases and FLT3-ITD, which is mediated by the SRC SH2 domain. We identified tyrosines 589 and 591 of FLT3-ITD to be essential for SRC binding and subsequent STAT5 activation. Using site-specific Abs, we found that both residues were significantly more strongly phosphorylated in FLT3-ITD compared with FLT3-TKD. SRC inhibition and knock-down blocked STAT5 activation and proliferation induced by FLT3-ITD but not by FLT3-TKD. We conclude that SRC might be a therapeutic target in FLT3-ITD+ AML.

scholarly journals The C-Terminus of c-Abl Is Required for Proliferation and Viability Signaling in a c-Abl/Erythropoietin Receptor Fusion Protein

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3848-3856 ◽  
Author(s):  
K. Okuda ◽  
A. D’Andrea ◽  
R.A. Van Etten ◽  
J.D. Griffin
Keyword(s):  
Transmembrane Domain ◽  
Biological Effects ◽  
Sh2 Domain ◽  
Binding Domain ◽  
Erythropoietin Receptor ◽  
Myelogenous Leukemia ◽  
Actin Binding ◽  
Time To Death ◽  
Actin Binding Domain

Activated ABL oncogenes cause B-cell leukemias in mice and chronic myelogenous leukemia in humans. However, the mechanism of transformation is complex and not well understood. A method to rapidly and reversibly activate c-ABL was created by fusing the extra-cytoplasmic and transmembrane domain of the erythropoietin (EPO) receptor with c-ABL (EPO R/ABL). When this chimeric receptor was expressed in Ba/F3 cells, the addition of EPO resulted in a dose-dependent activation of c-ABL tyrosine kinase and was strongly antiapoptotic and weakly mitogenic. To evaluate the contributions of various ABL domains to biochemical signaling and biological effects, chimeric receptors were constructed in which the ABL SH3 domain was deleted (▵SH3), the SH2 domain was deleted (▵SH2), the C-terminal actin-binding domain was deleted (▵ABD), or kinase activity was eliminated by a point mutation, K290M (KD). The mutant receptors were stably expressed in Ba/F3 cells and analyzed for signaling defects, proliferation, viability, and EPO-induced leukemia in nude mice. When compared with the ability of the full-length EPO R/ABL receptor to induce proliferation and support viability in vitro, the ▵SH3 mutant was equivalent, the ▵SH2 mutant was moderately impaired, and the ▵ABD and KD mutants were profoundly impaired. None of these cell lines caused leukemia in mice in the absence of pharmacological doses of EPO. However, in mice treated with EPO (10 U/d), death from leukemia occurred rapidly with wild-type and ▵SH3. However, time to death was prolonged by at least twofold for ▵SH2 and greater than threefold for ▵ABD. This inducible model of ABL transformation provides a method to link specific signaling defects with specific biological defects and has shown an important role for the C-terminal actin-binding domain in proliferation and transformation in the context of this receptor/oncogene.

scholarly journals Association of p62, a multifunctional SH2- and SH3-domain-binding protein, with src family tyrosine kinases, Grb2, and phospholipase C gamma-1.

1995 ◽  
Vol 15 (1) ◽  
pp. 186-197 ◽  
Author(s):  
S Richard ◽  
D Yu ◽  
K J Blumer ◽  
D Hausladen ◽  
M W Olszowy ◽  
...  
Keyword(s):  
Phospholipase C ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Sh3 Domain ◽  
Sh2 Domain ◽  
Src Family Kinases ◽  
Src Family Kinase ◽  
Sh3 Domains ◽  
Sh2 Domains ◽  
Src Family Tyrosine Kinases

src family tyrosine kinases contain two noncatalytic domains termed src homology 3 (SH3) and SH2 domains. Although several other signal transduction molecules also contain tandemly occurring SH3 and SH2 domains, the function of these closely spaced domains is not well understood. To identify the role of the SH3 domains of src family tyrosine kinases, we sought to identify proteins that interacted with this domain. By using the yeast two-hybrid system, we identified p62, a tyrosine-phosphorylated protein that associates with p21ras GTPase-activating protein, as a src family kinase SH3-domain-binding protein. Reconstitution of complexes containing p62 and the src family kinase p59fyn in HeLa cells demonstrated that complex formation resulted in tyrosine phosphorylation of p62 and was mediated by both the SH3 and SH2 domains of p59fyn. The phosphorylation of p62 by p59fyn required an intact SH3 domain, demonstrating that one function of the src family kinase SH3 domains is to bind and present certain substrates to the kinase. As p62 contains at least five SH3-domain-binding motifs and multiple tyrosine phosphorylation sites, p62 may interact with other signalling molecules via SH3 and SH2 domain interactions. Here we show that the SH3 and/or SH2 domains of the signalling proteins Grb2 and phospholipase C gamma-1 can interact with p62 both in vitro and in vivo. Thus, we propose that one function of the tandemly occurring SH3 and SH2 domains of src family kinases is to bind p62, a multifunctional SH3 and SH2 domain adapter protein, linking src family kinases to downstream effector and regulatory molecules.

scholarly journals Phosphotyrosine-dependent interaction of SHC and insulin receptor substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2 domain.

1995 ◽  
Vol 15 (5) ◽  
pp. 2500-2508 ◽  
Author(s):  
T A Gustafson ◽  
W He ◽  
A Craparo ◽  
C D Schaub ◽  
T J O'Neill
Keyword(s):  
Insulin Receptor ◽  
Mutational Analysis ◽  
Sh2 Domain ◽  
Binding Domain ◽  
Homologous Region ◽  
Juxtamembrane Domain ◽  
Atp Binding Site ◽  
Protein Protein Interaction ◽  
Binding Domains ◽  
Src Homology 2 Domain

The SHC proteins have been implicated in insulin receptor (IR) signaling. In this study, we used the sensitive two-hybrid assay of protein-protein interaction to demonstrate that SHC interacts directly with the IR. The interaction is mediated by SHC amino acids 1 to 238 and is therefore independent of the Src homology 2 domain. The interaction is dependent upon IR autophosphorylation, since the interaction is eliminated by mutation of the IR ATP-binding site. In addition, mutational analysis of the Asn-Pro-Glu-Tyr (NPEY) motif within the juxtamembrane domain of the IR showed the importance of the Asn, Pro, and Tyr residues to both SHC and IR substrate 1 (IRS-1) binding. We conclude that SHC interacts directly with the IR and that phosphorylation of Tyr-960 within the IR juxtamembrane domain is necessary for efficient interaction. This interaction is highly reminiscent of that of IRS-1 with the IR, and we show that the SHC IR-binding domain can substitute for that of IRS-1 in yeast and COS cells. We identify a homologous region within the IR-binding domains of SHC and IRS-1, which we term the SAIN (SHC and IRS-1 NPXY-binding) domain, which may explain the basis of these interactions. The SAIN domain appears to represent a novel motif which is able to interact with autophosphorylated receptors such as the IR.

scholarly journals Novel autophosphorylation sites of Src family kinases regulate kinase activity and SH2 domain-binding capacity

FEBS Letters ◽  
2016 ◽  
Vol 590 (8) ◽  
pp. 1042-1052 ◽  
Author(s):  
Marion E. Weir ◽  
Jacqueline E. Mann ◽  
Thomas Corwin ◽  
Zachary W. Fulton ◽  
Jennifer M. Hao ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Binding Capacity ◽  
Sh2 Domain ◽  
Src Family Kinases

scholarly journals The C-Terminus of c-Abl Is Required for Proliferation and Viability Signaling in a c-Abl/Erythropoietin Receptor Fusion Protein

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3848-3856 ◽  
Author(s):  
K. Okuda ◽  
A. D’Andrea ◽  
R.A. Van Etten ◽  
J.D. Griffin
Keyword(s):  
Transmembrane Domain ◽  
Biological Effects ◽  
Sh2 Domain ◽  
Binding Domain ◽  
Erythropoietin Receptor ◽  
Myelogenous Leukemia ◽  
Actin Binding ◽  
Time To Death ◽  
Actin Binding Domain

Abstract Activated ABL oncogenes cause B-cell leukemias in mice and chronic myelogenous leukemia in humans. However, the mechanism of transformation is complex and not well understood. A method to rapidly and reversibly activate c-ABL was created by fusing the extra-cytoplasmic and transmembrane domain of the erythropoietin (EPO) receptor with c-ABL (EPO R/ABL). When this chimeric receptor was expressed in Ba/F3 cells, the addition of EPO resulted in a dose-dependent activation of c-ABL tyrosine kinase and was strongly antiapoptotic and weakly mitogenic. To evaluate the contributions of various ABL domains to biochemical signaling and biological effects, chimeric receptors were constructed in which the ABL SH3 domain was deleted (▵SH3), the SH2 domain was deleted (▵SH2), the C-terminal actin-binding domain was deleted (▵ABD), or kinase activity was eliminated by a point mutation, K290M (KD). The mutant receptors were stably expressed in Ba/F3 cells and analyzed for signaling defects, proliferation, viability, and EPO-induced leukemia in nude mice. When compared with the ability of the full-length EPO R/ABL receptor to induce proliferation and support viability in vitro, the ▵SH3 mutant was equivalent, the ▵SH2 mutant was moderately impaired, and the ▵ABD and KD mutants were profoundly impaired. None of these cell lines caused leukemia in mice in the absence of pharmacological doses of EPO. However, in mice treated with EPO (10 U/d), death from leukemia occurred rapidly with wild-type and ▵SH3. However, time to death was prolonged by at least twofold for ▵SH2 and greater than threefold for ▵ABD. This inducible model of ABL transformation provides a method to link specific signaling defects with specific biological defects and has shown an important role for the C-terminal actin-binding domain in proliferation and transformation in the context of this receptor/oncogene.

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