scholarly journals APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl

Leukemia ◽  
1999 ◽  
Vol 13 (5) ◽  
pp. 760-767 ◽  
Author(s):  
T Wakioka ◽  
A Sasaki ◽  
K Mitsui ◽  
M Yokouchi ◽  
A Inoue ◽  
...  
Keyword(s):  
Adaptor Protein ◽  
Pleckstrin Homology ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Src Homology ◽  
Stat Pathway

scholarly journals PLC-γ directly binds activated c-Src, which is necessary for carbachol-mediated inhibition of NHE3 activity in Caco-2/BBe cells

2013 ◽  
Vol 305 (3) ◽  
pp. C266-C275 ◽  
Author(s):  
Nicholas C. Zachos ◽  
Luke J. Lee ◽  
Olga Kovbasnjuk ◽  
Xuhang Li ◽  
Mark Donowitz
Keyword(s):  
Sh2 Domain ◽  
Signaling Proteins ◽  
Multiprotein Complexes ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Src Inhibitor ◽  
Intracellular Ca ◽  
Direct Binding ◽  
Src Homology

Elevated levels of intracellular Ca2+([Ca2+]i) inhibit Na+/H+exchanger 3 (NHE3) activity in the intact intestine. We previously demonstrated that PLC-γ directly binds NHE3, an interaction that is necessary for [Ca2+]iinhibition of NHE3 activity, and that PLC-γ Src homology 2 (SH2) domains may scaffold Ca2+signaling proteins necessary for regulation of NHE3 activity. [Ca2+]iregulation of NHE3 activity is also c-Src dependent; however, the mechanism by which c-Src is involved is undetermined. We hypothesized that the SH2 domains of PLC-γ might link c-Src to NHE3-containing complexes to mediate [Ca2+]iinhibition of NHE3 activity. In Caco-2/BBe cells, carbachol (CCh) decreased NHE3 activity by ∼40%, an effect abolished with the c-Src inhibitor PP2. CCh treatment increased the amount of active c-Src as early as 1 min through increased Y416phosphorylation. Coimmunoprecipitation demonstrated that c-Src associated with PLC-γ, but not NHE3, under basal conditions, an interaction that increased rapidly after CCh treatment and occurred before the dissociation of PLC-γ and NHE3 that occurred 10 min after CCh treatment. Finally, direct binding to c-Src only occurred through the PLC-γ SH2 domains, an interaction that was prevented by blocking the PLC-γ SH2 domain. This study demonstrated that c-Src 1) activity is necessary for [Ca2+]iinhibition of NHE3 activity, 2) activation occurs rapidly (∼1 min) after CCh treatment, 3) directly binds PLC-γ SH2 domains and associates dynamically with PLC-γ under elevated [Ca2+]iconditions, and 4) does not directly bind NHE3. Under elevated [Ca2+]iconditions, PLC-γ scaffolds c-Src into NHE3-containing multiprotein complexes before dissociation of PLC-γ from NHE3 and subsequent endocytosis of NHE3.

scholarly journals Calcium Release at Fertilization in Starfish Eggs Is Mediated by Phospholipase Cγ

1997 ◽  
Vol 138 (6) ◽  
pp. 1303-1311 ◽  
Author(s):  
David J. Carroll ◽  
Chodavarapu S. Ramarao ◽  
Lisa M. Mehlmann ◽  
Serge Roche ◽  
Mark Terasaki ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Calcium Release ◽  
Specific Inhibitor ◽  
Sh2 Domain ◽  
High Concentration ◽  
Serotonin 2C Receptor ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Src Homology ◽  
Domain Protein

Although inositol trisphosphate (IP3) functions in releasing Ca2+ in eggs at fertilization, it is not known how fertilization activates the phospholipase C that produces IP3. To distinguish between a role for PLCγ, which is activated when its two src homology-2 (SH2) domains bind to an activated tyrosine kinase, and PLCβ, which is activated by a G protein, we injected starfish eggs with a PLCγ SH2 domain fusion protein that inhibits activation of PLCγ. In these eggs, Ca2+ release at fertilization was delayed, or with a high concentration of protein and a low concentration of sperm, completely inhibited. The PLCγSH2 protein is a specific inhibitor of PLCγ in the egg, since it did not inhibit PLCβ activation of Ca2+ release initiated by the serotonin 2c receptor, or activation of Ca2+ release by IP3 injection. Furthermore, injection of a PLCγ SH2 domain protein mutated at its phosphotyrosine binding site, or the SH2 domains of another protein (the phosphatase SHP2), did not inhibit Ca2+ release at fertilization. These results indicate that during fertilization of starfish eggs, activation of phospholipase Cγ by an SH2 domain-mediated process stimulates the production of IP3 that causes intracellular Ca2+ release.

scholarly journals Adaptor Protein 3BP2 Is a Potential Ligand of Src Homology 2 and 3 Domains of Lyn Protein-tyrosine Kinase

2003 ◽  
Vol 278 (27) ◽  
pp. 24912-24920 ◽  
Author(s):  
Koichiro Maeno ◽  
Kiyonao Sada ◽  
Shinkou Kyo ◽  
S. M. Shahjahan Miah ◽  
Keiko Kawauchi-Kamata ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Adaptor Protein ◽  
Protein Tyrosine ◽  
Src Homology 2 ◽  
Src Homology ◽  
Potential Ligand

Regulation of class IA PI3Ks

2007 ◽  
Vol 35 (2) ◽  
pp. 242-244 ◽  
Author(s):  
H. Wu ◽  
Y. Yan ◽  
J.M. Backer
Keyword(s):  
Tyrosine Kinases ◽  
Regulatory Subunit ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Pi3k Activity ◽  
Wide Range ◽  
Rho Family Gtpases ◽  
Src Homology ◽  
Rho Family

Class IA PI3Ks (phosphoinositide 3-kinases) regulate a wide range of cellular responses through the production of PI(3,4,5)P3 (phosphatidylinositol 3,4,5-trisphosphate) in cellular membranes. They are activated by receptor tyrosine kinases, by Ras and Rho family GTPases, and in some cases by Gβγ subunits from trimeric G-proteins. Crystallographic studies on the related class IB PI3Kγ, and biochemical and structural studies on the class IA PI3Ks, have led to new insights into how these critical enzymes are regulated in normal cells and how mutations can lead to their constitutive activation in transformed cells. The present paper will discuss recent studies on the regulation of class I (p85/p110) PI3Ks, with a focus on the role of SH2 domains (Src homology 2 domains) in the p85 regulatory subunit in modulating PI3K activity.

scholarly journals Phosphatidylinositol 3-kinase associates, via its Src homology 2 domains, with the activated erythropoietin receptor

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3204-3210 ◽  
Author(s):  
JE Damen ◽  
AL Mui ◽  
L Puil ◽  
T Pawson ◽  
G Krystal
Keyword(s):  
Erythropoietin Receptor ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Protein Substrates ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Src Homology ◽  
Specific Association ◽  
Phosphatidylinositol 3

The erythropoietin receptor (EpR) belongs to a family of hematopoietin receptors whose members lack tyrosine kinase activity. Nonetheless, within minutes of binding Ep, a number of cellular proteins become transiently phosphorylated on tyrosine residues. One of these proteins, as we and others have shown previously, is the EpR itself. To identify the remaining protein substrates, we have examined the antiphosphotyrosine immunoprecipitates of lysates from Ba/F3 cells expressing high levels of cell surface EpRs. We now present data showing that, in response to Ep, the 85-Kd regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase) becomes immunoprecipitable with antiphosphotyrosine antibodies. This appears to be due, in large part, to the specific association of PI 3-kinase with the tyrosine- phosphorylated EpR, either directly or through a 93- or 70-Kd tyrosine- phosphorylated intermediate. The activity of this EpR associated PI 3- kinase, assessed in anti-EpR immunoprecipitates, is maximal within 2 minutes of incubation with Ep and returns almost to baseline levels by 10 minutes. In vitro studies suggest that the interaction between PI 3- kinase and the activated EpR is mediated by the N- and C-terminal SH2 domains of p85 and tyrosine-phosphorylated motifs on the EpR.

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