Journal
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
Volume 1747, Issue 1, Pages 1-25Publisher
ELSEVIER
DOI: 10.1016/j.bbapap.2004.10.005
Keywords
protein tyrosine kinase; signal transduction; SH2 inhibitor; phosphotyrosine mimetic
Categories
Funding
- NCI NIH HHS [CA094378, CA107785, CA82258, R21 CA107785] Funding Source: Medline
Ask authors/readers for more resources
The Src homology 2 (SH2) domain is the most prevalent protein binding module that recognizes phosphotyrosine. This similar to100-aminoacid domain is highly conserved structurally despite being found in a wide variety proteins. Depending on the nature of neighboring protein module(s), such as catalytic domains and other protein binding domains, SH2-containing proteins play many different roles in cellular protein tyrosine kinase (PTK) signaling pathways. Accumulating evidence indicates SH2 domains are highly versatile and exhibit considerable flexibility in how they bind to their ligands. To illustrate this functional versatility, we present three specific examples: the SAP, Cbl and SOCS families of SH2-containing proteins, which play key roles in immune responses, termination of PTK signaling, and cytokine responses. In addition, we highlight current progress in the development of SH2 domain inhibitors designed to antagonize or modulate PTK signaling in human disease. Inhibitors of the Grb2 and Src SH2 domains have been extensively studied, with the aim of targeting the Ras pathway and osteoclastic bone resorption, respectively. Despite formidable difficulties in drug design due to the lability and poor cell permeability of negatively charged phosphorylated SH2 ligands, a variety of structure-based strategies have been used to reduce the size, charge and peptide character of such ligands, leading to the development of high-affinity lead compounds with potent cellular activities. These studies have also led to new insights into molecular recognition by the SH2 domain. (C) 2004 Elsevier B.V. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available