%0 Journal Article
%T Gab Adapter Proteins as Therapeutic Targets for Hematologic Disease
%A Sheetal Verma
%A Tamisha Vaughan
%A Kevin D. Bunting
%J Advances in Hematology
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/380635
%X The Grb-2 associated binder (Gab) family of scaffolding/adaptor/docking proteins is a group of three molecules with significant roles in cytokine receptor signaling. Gabs possess structural motifs for phosphorylation-dependent receptor recruitment, Grb2 binding, and activation of downstream signaling pathways through p85 and SHP-2. In addition, Gabs participate in hematopoiesis and regulation of immune response which can be aberrantly activated in cancer and inflammation. The multifunctionality of Gab adapters might suggest that they would be too difficult to consider as candidates for ¡°targeted¡± therapy. However, the one drug/one target approach is giving way to the concept of one drug/multiple target approach since few cancers are addicted to a single signaling molecule for survival and combination drug therapies can be problematic. In this paper, we cover recent findings on Gab multi-functionality, binding partners, and their role in hematological malignancy and examine the concept of Gab-targeted therapy. 1. Discovery and Similarities of Gab Family Members The Gab proteins, Gab1, Gab2, and Gab3, comprise a family of scaffolding/docking molecules involved in multiple signaling pathways mediated by receptor tyrosine kinases (RTKs) and non-RTK receptors. Gab proteins integrate and amplify signals from a wide variety of sources including growth factor, cytokine, and antigen receptors, as well as cell adhesion molecules. They are subject to complex regulation by feedforward and feedback phosphorylation events as well as protein-protein interactions. Gab proteins range from 50 to 100£¿kDa in size [1] and were originally identified as the mammalian homologs of the daughter of sevenless (DOS) Drosophila adapter proteins [2, 3]. They also display sequence similarity to Suppressor of Clear 1 (Soc1), which was identified by genetic screen in C. elegans [3, 4]. Gab1 was originally identified as a binding protein for Grb-2 [5], and Gab2 was isolated by the purification of a binding partner for SHP [6]. The discovery of Gab3 was aided by a large sequencing project, and its isolation was based on sequence similarities to Gab1 and Gab2 [7]. Very recent entries at both the genomic DNA and transcript level have been recorded for Gab4 gene in both humans and chimpanzees, but this gene is not present in mice. The human Gab4 gene is located on chromosome 22q11.1 and its nucleotide sequence is most related to Gab2 [8]. The overall sequence homology between Gab family members is about 40¨C50%. All Gab proteins share a similar modular structure, including a Pleckstrin
%U http://www.hindawi.com/journals/ah/2012/380635/