Date Published: December 14, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Sheetal Verma, Tamisha Vaughan, Kevin D. Bunting.
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.
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  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].
As mentioned above, one of the fundamental mechanisms for regulation of Gab-mediated signal transduction is site-specific tyrosine phosphorylation of these proteins. These molecules are involved in the phosphatidylinositol-3 kinase (PI3-K) and mitogen-associated protein kinase (MAPK) pathways and include multiple protein binding sites . To further elaborate, Figure 2 illustrates how Gab2 is involved in PI-3K and MAPK pathways. These proteins are tyrosine phosphorylated following cytokine stimulation which enables interaction with a large number of partners. Table 1 summarizes a few key receptors which are associated with hematopoiesis, some of which are also found mutated in association with hematologic malignancy. Serine phosphorylation of Gabs by downstream effectors also has been described [19, 20], which will be discussed later.
Given their integral role in cytokine signaling, it was proposed that Gabs may play important roles in hematopoiesis. However, to date, very little is known about how multiple Gabs regulate hematopoietic cytokine signaling.
It is well established that Gab proteins promote tumor-genesis by functioning as “accomplices” of certain oncoproteins or by amplifying signaling upon their overexpression. This type of “nononcogene addiction” has been described for molecules that become essential in the setting of cancer, but they are not mutated or capable of transformation on their own. In addition to normal cytokine activation, Gab1 and Gab2 can also be activated by oncogenic tyrosine kinases, oncoproteins, and Src family kinases (summarized in Table 2). Gab3 has not yet been described to play a role in cancer signaling.
The key to figuring out the role of Gabs in hematological disease is to understand their role in signaling cascades. It is crucial to visualize these as intertwined loops. Firstly, phosphorylation of a particular residue might affect the phosphorylation of a nearby residue in either a positive or antagonistic fashion, due to phosphorylation-induced changes in protein conformation. Secondly, phosphorylation-induced conformational changes may alter the accessibility of key regions, such as the PH domain.
Since Gabs bind many common receptors and are much less studied in hematopoiesis, it is pivotal to understand the role of binding to their partners and how it impacts oncogenic tyrosine kinase signaling. Due to the fact that all three family members are potential players in various signaling pathways, it will be interesting to see the shift in approach for targeting the Gab family. As discussed earlier, total knockdown of these proteins has varied physiological and phenotypic impacts. But, it cannot be emphasized enough that the Gab family members are also key regulators/enhancers of other oncogenic proteins and could compensate for the deficit of a family member.