scholarly journals HIV-1 Nef Selectively Activates Src Family Kinases Hck, Lyn, and c-Src through Direct SH3 Domain Interaction

2006 ◽  
Vol 281 (37) ◽  
pp. 27029-27038 ◽  
Author(s):  
Ronald P. Trible ◽  
Lori Emert-Sedlak ◽  
Thomas E. Smithgall
Keyword(s):  
Sh3 Domain ◽  
Src Family Kinases ◽  
Domain Interaction ◽  
Hiv 1

In vitro binding activity between HCK SH3 domain and HIV-1 Nef protein

2011 ◽  
Vol 31 (3) ◽  
pp. 262-265
Author(s):  
Xiao-lin QIN ◽  
Chao-qi LIU ◽  
Dong-ming REN ◽  
Yong-qin ZHOU
Keyword(s):  
Sh3 Domain ◽  
Binding Activity ◽  
Hiv 1

scholarly journals Competitive displacement of full-length HIV-1 Nef from the Hck SH3 domain by a high-affinity artificial peptide

2007 ◽  
Vol 388 (6) ◽  
pp. 611-615 ◽  
Author(s):  
Thomas Stangler ◽  
Tuyen Tran ◽  
Silke Hoffmann ◽  
Holger Schmidt ◽  
Esther Jonas ◽  
...  
Keyword(s):  
Nmr Spectroscopy ◽  
Phage Display ◽  
Dissociation Constant ◽  
Sh3 Domain ◽  
Competitive Displacement ◽  
Ligand Interaction ◽  
High Affinity ◽  
Hematopoietic Cell Kinase ◽  
Proline Rich Peptide ◽  
Hiv 1

AbstractWe studied the interaction of the artificial 12-aa proline-rich peptide PD1 with the SH3 domain of the hematopoietic cell kinase Hck and the peptide's potency in competitively displacing HIV-1 Nef from the Hck SH3 domain. PD1 was obtained from a phage display screen and exhibits exceptional affinity for the Hck SH3 domain (Kd=0.23 μM). Competition experiments using NMR spectroscopy demonstrate that the peptide even displaces Nef from Hck SH3 and allow for estimation of the Nef-Hck SH3 dissociation constant (Kd=0.44 μM), the strongest SH3 ligand interaction known so far. Consequences of this study for novel antiviral concepts are discussed.

scholarly journals Differential Sensitivity of Src-Family Kinases to Activation by SH3 Domain Displacement

PLoS ONE ◽  
2014 ◽  
Vol 9 (8) ◽  
pp. e105629 ◽  
Author(s):  
Jamie A. Moroco ◽  
Jodi K. Craigo ◽  
Roxana E. Iacob ◽  
Thomas E. Wales ◽  
John R. Engen ◽  
...  
Keyword(s):  
Sh3 Domain ◽  
Src Family Kinases ◽  
Differential Sensitivity

Phosphatidylinositol (PI) 3-kinase and PI 4-kinase binding to the CD4-p56lck complex: the p56lck SH3 domain binds to PI 3-kinase but not PI 4-kinase

1993 ◽  
Vol 13 (12) ◽  
pp. 7708-7717
Author(s):  
K V Prasad ◽  
R Kapeller ◽  
O Janssen ◽  
H Repke ◽  
J S Duke-Cohan ◽  
...  
Keyword(s):  
T Cells ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Sh3 Domain ◽  
Sh2 Domain ◽  
Activation Process ◽  
Lipid Kinase ◽  
Sh3 Domains ◽  
Protein Tyrosine ◽  
Hiv 1

CD4 serves as a receptor for major histocompatibility complex class II antigens and as a receptor for the human immunodeficiency virus type 1 (HIV-1) viral coat protein gp120. It is coupled to the protein-tyrosine kinase p56lck, an interaction necessary for an optimal response of certain T cells to antigen. In addition to the protein-tyrosine kinase domain, p56lck possesses Src homology 2 and 3 (SH2 and SH3) domains as well as a unique N-terminal region. The mechanism by which p56lck generates intracellular signals is unclear, although it has the potential to interact with various downstream molecules. One such downstream target is the lipid kinase phosphatidylinositol 3-kinase (PI 3-kinase), which has been found to bind to activated pp60src and receptor-tyrosine kinases. In this study, we verified that PI 3-kinase associates with the CD4:p56lck complex as judged by the presence of PI 3-phosphate generated from anti-CD4 immunoprecipitates and detected by high-pressure liquid chromatographic analysis. However, surprisingly, CD4-p56lck was also found to associate with another lipid kinase, phosphatidylinositol 4-kinase (PI 4-kinase). The level of associated PI 4-kinase was generally higher than PI 3-kinase activity. HIV-1 gp120 and antibody-mediated cross-linking induced a 5- to 10-fold increase in the level of CD4-associated PI 4- and PI 3-kinases. The use of glutathione S-transferase fusion proteins carrying Lck-SH2, Lck-SH3, and Lck-SH2/SH3 domains showed PI 3-kinase binding to the SH3 domain of p56lck, an interaction facilitated by the presence of an adjacent SH2 domain. PI 4-kinase bound to neither the SH2 nor the SH3 domain of p56lck. CD4-p56lck contributes PI 3- and PI 4-kinase to the activation process of T cells and may play a role in HIV-1-induced immune defects.

Abstract B190: Allosteric modulation of Src family kinases via SH3 domain displacement

2015 ◽  
Author(s):  
Heather L. Rust ◽  
Jamie A. Moroco ◽  
John J. Alvarado ◽  
John J. Engen ◽  
Thomas E. Smithgall
Keyword(s):  
Sh3 Domain ◽  
Allosteric Modulation ◽  
Src Family Kinases

scholarly journals Regulation of Src Family Kinases in Human Cancers

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Banibrata Sen ◽  
Faye M. Johnson
Keyword(s):  
Cancer Cells ◽  
Protein Tyrosine Kinase ◽  
Epithelial To Mesenchymal Transition ◽  
Src Family Kinases ◽  
Domain Interaction ◽  
Mesenchymal Transition ◽  
Human Cancers ◽  
Src Inhibitor ◽  
Promising Target ◽  
The Status

The nonreceptor protein tyrosine kinase Src plays a crucial role in the signal transduction pathways involved in cell division, motility, adhesion, and survival in both normal and cancer cells. Although the Src family kinases (SFKs) are activated in various types of cancers, the exact mechanisms through which they contribute to the progression of individual tumors remain to be defined. The activation of Src in human cancers may occur through a variety of mechanisms that include domain interaction and structural remodeling in response to various activators or upstream kinases and phosphatastes. Because of Src's prominent roles in invasion and tumor progression, epithelial-to-mesenchymal transition, angiogenesis, and the development of metastasis, Src is a promising target for cancer therapy. Several small molecule inhibitors of Src are currently being investigated in clinical trials. In this article, we will summarize the mechanisms regulating Src kinase activity in normal and cancer cells and discuss the status of Src inhibitor development against various types of cancers.

In silico screening and biological evaluation of inhibitors of Src-SH3 domain interaction with a proline-rich ligand

2008 ◽  
Vol 18 (3) ◽  
pp. 1217-1222 ◽  
Author(s):  
Noor Atatreh ◽  
Cvetan Stojkoski ◽  
Phillippa Smith ◽  
Grant W. Booker ◽  
Caroline Dive ◽  
...  
Keyword(s):  
In Silico ◽  
Sh3 Domain ◽  
Biological Evaluation ◽  
Domain Interaction ◽  
In Silico Screening

scholarly journals Differential Regulation of Src Family Kinases by HIV‐1 Nef

2006 ◽  
Vol 20 (5) ◽  
Author(s):  
Ronald P. Trible ◽  
Thomas E. Smithgall
Keyword(s):  
Differential Regulation ◽  
Src Family Kinases ◽  
Hiv 1

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.

Sign in / Sign up

Export Citation Format

Share Document